Uveal melanoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D., Simrat Sarai, M.D. [2]

Uveal melanoma is a rare cancer arising from melanocytes of the eye involving the iris, ciliary body, or choroid. Iris melanomas are less common than choroidal melanomas. Uveal melanoma may be classified according to cell type into 5 subtypes: Spindle A, spindle B, epitheliolid, mixed, and necrotic. Uveal melanoma may also be classified according to its location into 2 types, anterior uveal melanoma which contain iris melanoma, and posterior uveal melanoma which contains ciliary body melanoma and chroidal melanoma.Activating mutations in GNAQ or GNA11, genes encoding for G protein alpha subunits. These mutations lead to activation of downstream signaling pathways including the MAPK pathway in uveal melanoma. Inactivating somatic mutations are present in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1. The mutations in the gene BAP1 are strongly linked to metastatic spread and patient survival. The incidence of uveal melanoma in the United States is approximately 0.43 per 100, 000 individuals. The incidence of uveal melanoma is approximately .53 to 1.09 cases per 100, 000 individuals worldwide. The incidence of uveal melanoma increases with age; the median age at diagnosis is 70 years. Males are more commonly affected with uveal melanoma than females. The incidence of uveal melanoma in males and females is approximately 0.49 and 0.37 per 100,000 individuals respectively. Uveal melanoma usually affects individuals of the caucasians race. Common risk factors in the development of uveal melanoma include advanced age, male gender, white race, genetic, ocular nevi, pregnancy, impaired immune system, light colored iris, sunlight exposure, and trauma.If left untreated, 50% of patients with uveal melanoma may progress to develop metastasis. Common complications of uveal melanoma include glaucoma, vision loss, and metastasis. Prognosis is generally good for patients with iris melanoma, and the 10 year-survival for iris melanoma is approximately 95 percent and for ciliochoroidal tumors is 77 percent respectively. A positive history of pre-existing iris nevus which increased in size, eye pain, visual loss, blurred vision, floaters, age between 50_70 years old, male gender, white race, pregnancy, impaired immune system, light colored-irides, sunlight exposure, trauma, and fluorescent lighting exposure is suggestive of uveal melanoma. The most common symptoms of uveal melanoma include ,eye pain, blurred vision, eye redness, loss of peripheral vision, poor or blurry vision in one eye, a dark spot on the iris, seeing flashing lights, and floaters. The optimal therapy for uveal melanoma depends on the size of the tumor. Surgery is the mainstay of treatment for uveal melanoma. The following types of surgery may be used resection, enucleation, and exenteration. Pharmacologic medical therapy is recommended among patients with metastatic disease and include chemotherapy, immunotherapy, and targeted therapy.

Uveal melanoma was first discovered by two Scottish surgeons, Allan Burns (1781–1813) and James Wardrop (1782–1869). Allan Burns described the first patients with uveal melanoma, Mrs Scot who had painless blindness in one eye and an opacity behind the lens.

Uveal melanoma may be classified according to cell type into 5 subtypes: Spindle A, spindle B, epitheliolid, mixed, and necrotic. Uveal melanoma may also be classified according to its location into 2 types, anterior uveal melanoma which contain iris melanoma, and posterior uveal melanoma which contains ciliary body melanoma and chroidal melanoma.

It is understood that uveal melanoma is the result of genetic mutations. Activating mutations in GNAQ or GNA11, genes encoding for G protein alpha subunits. These mutations lead to activation of downstream signaling pathways including the MAPK pathway in uveal melanoma. Inactivating somatic mutations are present in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1. The mutations in the gene BAP1 are strongly linked to metastatic spread and patient survival. Conditions associated with uveal melanoma include ocular nevi, impaired immune system, pregnancy, and trauma. On microscopic histopathological analysis, we have 5 subtypes according to cell type into: Spindle A, spindle B, epitheliolid, mixed, and necrotic.

Uveal melanoma is caused by a mutation in the DNA.

Uveal melanoma must be differentiated from retinoblastoma, coats disease, persistent fetal vasculature, astrocytic hamartoma, retinopathy of prematurity, ocular toxocariasis, familial exudative vitreoretinopathy, norrie’s disease, and coloboma.

The incidence of uveal melanoma in the United States is approximately 0.43 per 100, 000 individuals. The incidence of uveal melanoma is approximately .53 to 1.09 cases per 100, 000 individuals worldwide. The incidence of uveal melanoma increases with age; the median age at diagnosis is 70 years. Males are more commonly affected with uveal melanoma than females. The incidence of uveal melanoma in males and females is approximately 0.49 and 0.37 per 100,000 individuals respectively. Uveal melanoma usually affects individuals of the caucasians race.

Common risk factors in the development of uveal melanoma include advanced age, male gender, white race, genetic, ocular nevi, pregnancy, impaired immune system, light colored iris, sunlight exposure, and trauma.

According to the United States Preventive Services Task Force, screening for uveal melanoma is not recommended.

If left untreated, 50% of patients with uveal melanoma may progress to develop metastasis. Common complications of uveal melanoma include glaucoma, vision loss, and metastasis. Prognosis is generally good for patients with iris melanoma, and the 10 year-survival for iris melanoma is approximately 95 percent and for ciliochoroidal tumors is 77 percent respectively.

There is no single diagnostic study of choice for the diagnosis of uveal melanoma, but uveal melanoma can be diagnosed based on ophthalmologic examination and imaging.

A positive history of pre-existing iris nevus which increased in size, eye pain, visual loss, blurred vision, floaters, age between 50_70 years old, male gender, white race, pregnancy, impaired immune system, light colored-irides, sunlight exposure, trauma, and fluorescent lighting exposure is suggestive of uveal melanoma. The most common symptoms of uveal melanoma include ,eye pain, blurred vision, eye redness, loss of peripheral vision, poor or blurry vision in one eye, a dark spot on the iris, seeing flashing lights, and floaters.

Patients with uveal melanoma usually appear normal. Physical examination of patients with uveal melanoma is usually remarkable for ophthalmologic findings of melanoma.

Some patients with uveal melanoma may have elevated liver enzyme level, which is usually suggestive of metastasis.

There are no ECG findings associated with uveal melanoma.

There are no x-ray findings associated with uveal melanoma.

Ultrasound may be helpful in the diagnosis of uveal melanoma. Findings on an ultrasound suggestive of uveal melanoma include low reflectivity, vascularity inside the tumor, and acoustic hollowing. it can differentiate ciliary body cyst from tumor in lesions larger than 3 mm.

CT scan may be helpful in the diagnosis of uveal. Findings on CT scan suggestive of uveal melanoma include elevated mushroom shaped lesions, hyper-dense, and contrastenhancement.

MRI may be helpful in the diagnosis of uveal melanoma. Findings on MRI suggestive of uveal melanoma include high intensity mass lesion (due to melanin and hemorrhage) on T1, and low intensity mass lesion on T2. The lesion enhances with gadolinium.

PET scan, ultrasound biomicroscopy, optical coherence tomography, color fundus photography, fluorescein angiography, indocyanine green angiography, transillumination, and photography may be helpful in the diagnosis of uveal melanoma.

Biopsy may be helpful in the diagnosis of uveal melanoma.

Pharmacologic medical therapy is recommended among patients with metastatic disease and include chemotherapy, immunotherapy, and targeted therapy.

Surgery is the mainstay of treatment for uveal melanoma. The following types of surgery may be used resection, enucleation, and exenteration.

There is no established method for prevention of uveal melanoma.

There are no established measures for the secondary prevention of uveal melanoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Uveal melanoma was first discovered by two Scottish surgeons, Allan Burns (1781–1813) and James Wardrop (1782–1869). Allan Burns described the first patients with uveal melanoma, Mrs Scot who had painless blindness in one eye and an opacity behind the lens.

• Uveal melanoma was first discovered by two Scottish surgeons, Allan Burns (1781–1813) and James Wardrop (1782–1869).^[1]
• Allan Burns described the first patients with uveal melanoma, Mrs Scot who had painless blindness in one eye and an opacity behind the lens.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D., Simrat Sarai, M.D. [2]

Uveal melanoma may be classified according to cell type into 5 subtypes: Spindle A, spindle B, epitheliolid, mixed, and necrotic. Uveal melanoma may also be classified according to its location into 2 types, anterior uveal melanoma which contain iris melanoma, and posterior uveal melanoma which contains ciliary body melanoma and chroidal melanoma.

Uveal melanoma may be classified according to cell type into 5 subtypes: Spindle A, spindle B, epitheliolid, mixed, and necrotic.^[1]

Cell type	Explanation
Spindle A	Fine nuclear chromatin Cells with small spindle nuclei and central dark stripe No distinct nucleoli Rare mitotic features
Spindle B	Commen Coarse nuclear chromatin Distinct nucleoli Rare mitotic features
Epithelioid	Rarest Large round nuclei Prominent nucleoli Mitotic features are common
Mixed	Most common Contains both spindle cells and epithelioil cells
Necrotic	uncommon Necrotic tumor with unidentifiable cell type

Uveal melanoma may also be classified according to its location into 2 types:

• Anterior uveal melanoma
  • Iris melanoma
• Posterior uveal melanoma
  • Ciliary body melanoma
  • Chroidal melanoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.,Simrat Sarai, M.D. [2]

It is understood that uveal melanoma is the result of genetic mutations. Activating mutations in GNAQ or GNA11, genes encoding for G protein alpha subunits. These mutations lead to activation of downstream signaling pathways including the MAPK pathway in uveal melanoma. Inactivating somatic mutations are present in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1. The mutations in the gene BAP1 are strongly linked to metastatic spread and patient survival. Conditions associated with uveal melanoma include ocular nevi, impaired immune system, pregnancy, and trauma. On microscopic histopathological analysis, we have 5 subtypes according to cell type into spindle A, spindle B, epitheliolid, mixed, and necrotic.

• Most of the uveal melanomas arise from a uveal nevi.^[1][2][3]

• It is understood that uveal melanoma is the result of genetic mutations.
• Uveal melanoma arises from melanocytes, which are normally involved in melanin production.

Genes involved in the pathogenesis of uveal melanoma include:

• Activating mutations in GNAQ or GNA11, genes encoding for G protein alpha subunits.^[1][2][3]
• These mutations lead to activation of downstream signaling pathways including the MAPK pathway in uveal melanoma.
• Inactivating somatic mutations are present in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1.
• The mutations in the gene BAP1 are strongly linked to metastatic spread and patient survival.^[4]
• In approximately five percent of patients with uveal melanomas germline mutations have been identified in BAP1, and these have been associated with involvement of the ciliary body and larger tumors.^[5]
• In approximately 18.6 percent of primary uveal melanomas recurring mutations occurring exclusively at codon 625 of the SF3B1 gene, encoding splicing factor 3B subunit 1 were identified.^[6]

Conditions associated with uveal melanoma include:^[7][8][9]

• Ocular nevi
• Impaired immune system
• Pregnancy
• Trauma

On microscopic histopathological analysis, we have 5 subtypes according to cell type include Spindle A, spindle B, epitheliolid, mixed, and necrotic.^[10]

Cell type	Explanation
Spindle A	Fine nuclear chromatin Cells with small spindle nuclei and central dark stripe No distinct nucleoli Rare mitotic features
Spindle B	Commen Coarse nuclear chromatin Distinct nucleoli Rare mitotic features
Epithelioid	Rarest Large round nuclei Prominent nucleoli Mitotic features are common
Mixed	Most common Contains both spindle cells and epithelioil cells
Necrotic	uncommon Necrotic tumor with unidentifiable cell type

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Uveal melanoma is caused by a mutation in the DNA.

Uveal melanoma is caused by a mutation in the DNA. These DNA mutations may be either inherited or acquired during life.^[1][2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Uveal melanoma must be differentiated from retinoblastoma, coats disease, persistent fetal vasculature, astrocytic hamartoma, retinopathy of prematurity, ocular toxocariasis, familial exudative vitreoretinopathy, norrie’s disease, and coloboma.

Uveal melanoma must be differentiated from retinoblastoma, coats disease, persistent fetal vasculature, astrocytic hamartoma, retinopathy of prematurity, ocular toxocariasis, familial exudative vitreoretinopathy, norrie’s disease, and coloboma.

Disease/Condition	Clinical presentation	Demographics/History	Diagnosis	Other notes
Uveal melanoma	Eye pain Blurred vision Eye redness Circumscribed nodule mostly in the inferior half of the iris Yellow or brown in color	Median age at diagnosis is 55 years Males are more commonly affected Mostly in caucasians race	History Ophtalmologic examination Ultrasound Acoustic hollowing Low reflectivity Vascularity inside the tumor Collar button shape CT/MRI	Associated with Impaired immune system Pregnancy Trauma
Retinoblastoma[1][2]	Retinal mass Gross examination reveals a whitish tumor with prominent vascularity Vitreous seeding in endophytic tumors exudative retinal detachment in exophytic tumor	Sporadic in 90% of the cases The median age of diagnosis is 18 months Bilateral in 70% of the cases	P/E: leukocoria Ultrasound imaging: A dome or placoid-shaped intraocular mass +/- intralesional calcification CT imaging: Presence of calcification within the tumor	Associated with 13q deletion syndrome
Coats’disease[3][4]	Yellowish appearance of leukocoria P/E: Exudative retinal detachment with vascular tortuosity and telangiectasia +/- neurovascular glaucoma Absence of calcification	Sporadic in 100% of the cases Almost always unilateral More common among boys The median age of diagnosis 5 to 9 years	P/E is diagnostic in most of the cases Ultrasound imaging: Complete retinal detachment Absence of calcification Exudative, mobile lipid material under retina	Fluorescein angiography reveals characteristic telangiectasias of small to medium-sized retinal vessels
Persistent fetal vasculature (formerly known as persistent hyperplastic primary vitreous)[4]	Presence of leukocoria in infancy which is commonly accompanied by microphthalmia Presence of retrolental fibrovascular tissue +/- secondary cataract	Sporadic in the majority of cases Always congenital (present at birth) Rarely bilateral	P/E: microphthalmia and increasedintraocular pressure Presence of elongated ciliary processes contracting into the retrolental mass Ultrasound imaging: Vitreous band from lens to optic nerve Short axial length of eyes	Bilateral cases has been accompanied byprotein C deficiency
Astrocytic hamartoma[5]	Presence of gray-yellow or translucent tumors involving the posterior pole near optic nerve	Presents at any age Some has been associated with neurofibromatosis type 1/tuberous sclerosis	P/E: A sessile shape tumor arising from the inner aspect of the sensory retina Presence of small areas of calcification/complete calcification in older patients	Reticular pattern of fine blood vessels on fluorescein angiography
Retinopathy of prematurity (ROP)[5]	Absence of calcification Presence of retinal contraction in one or both eyes	History of: Prematurity (< 32 weeks gestation) Low birth weight (< 1.5 kg/3.3 lbs) Oxygen supplementation Leukocoria is a late presentation of the disease Always bilateral	P/E: Bilateral retinal avascularity and non-perfusion in temporal peripheral retina with fibrovascular proliferation in advanced cases Ultrasound imaging: Retinal detachment with retinal bands	Short axial length of eyes
Ocular toxocariasis [5]	Presence of retinal and/or vitreous traction in approximately all of the cases	Presents at any age Mostly unilateral Ingestion of larvae leads to the infection	P/E: Presence of granuloma and retinal traction Ultrasound imaging: Peripheral mass Vitreoretinal band Traction retinal detachment Presence of eosinophils in the anterior chamber tap	Classified into three sub-types: Macular granuloma Peripheral granuloma Endophthalmitis
Familial Exudative Vitreoretinopathy (FEVR)[6]	Presents at birth The majority are asymptomatic May present with leukocoria, strabismus, and vision loss	Autosomal dominant pattern of inheritance May occur sporadically Findings include asymmetry of both eyes	P/E: Avascularity of the temporal retina with peripheral fibrovascular proliferation Fluorescein angiography: Peripheral non-perfusion of the fundus	Fundus findings are similar to retinopathy of prematurity except for the history of prematurity
Norrie’s Disease[5][7]	Presents with microcephaly, congenital blindness, deafness, and progressive neuropsychiatric illness	X-linked disorder More common in males	P/E: bilateral retinal dysplasia, sometimes with anterior segment abnormalities and microphthalmia	–
Coloboma[5]	Presents at birth Failure of the embryonic fissure to close completely results in an absence of normal retina and choroid	The majority are sporadic Congenital disorder that affects male and female equally May be unilateral or bilateral	P/E: Whitish depressed lesion of retina which is typically inferonasal and its margins may encompass the macula or optic nerve	It may be accompanied by CHARGE syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D., Simrat Sarai, M.D. [2]

The incidence of uveal melanoma in the United States is approximately 0.43 per 100, 000 individuals. The incidence of uveal melanoma is approximately .53 to 1.09 cases per 100, 000 individuals worldwide. The incidence of uveal melanoma increases with age; the median age at diagnosis is 70 years. Males are more commonly affected with uveal melanoma than females. The incidence of uveal melanoma in males and females is approximately 0.49 and 0.37 per 100,000 individuals respectively. Uveal melanoma usually affects individuals of the caucasians race.

• The incidence of uveal melanoma in the United States is approximately 0.43 per 100, 000 individuals. ^[1]
• The incidence of uveal melanoma is approximately 0.53 to 1.09 cases per 100, 000 individuals worldwide.

• The incidence of uveal melanoma increases with age; the median age at diagnosis is 55 years.^[2]

• Males are more commonly affected with uveal melanoma than females.
• The incidence of uveal melanoma in males and females is approximately 0.49 and 0.37 per 100,000 individuals respectively.^[1]

• Uveal melanoma usually affects individuals of the caucasians race.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Common risk factors in the development of uveal melanoma include advanced age, male gender, white race, genetic, ocular nevi, pregnancy, impaired immune system, light colored iris, sunlight exposure, and trauma.

Common risk factors in the development of uveal melanoma include advanced age, male gender, white race, genetic, ocular nevi, pregnancy, impaired immune system, light colored iris, sunlight exposure, and trauma.

• Common risk factors in the development of uveal melanoma include:^{[1][2][3][4][5][6][7][8][9]}
  • Age: (The mean age for uveal melanoma is 55 years old and its incidence drops after 70 years of age)
  • Male gender
  • Race: Whites are more commonly affected by uveal melanoma than blacks.
  • Genetic
  • Ocular nevi
  • Hormones: Pregnancy may increase the incidence of uveal melanoma.
  • Impaired immune system
  • light colored-irides
  • Sunlight exposure
  • Trauma

• Less common risk factors in the development of uveal melanoma include:^[10][11]
  • Melanocytosis
  • Fluorescent lighting
  • Viruses (togavirus)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

According to the United States Preventive Services Task Force, screening for uveal melanoma is not recommended.

• According to the United States Preventive Services Task Force, screening for uveal melanoma is not recommended.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

If left untreated, 50% of patients with uveal melanoma may progress to develop metastasis. Common complications of uveal melanoma include glaucoma, vision loss, and metastasis. Prognosis is generally good for patients with iris melanoma, and the 10 year-survival for iris melanoma is approximately 95 percent and for ciliochoroidal tumors is 77 percent respectively.

• The clinical course is unpredictable and metastatic disease can develop very late after a long disease-free interval. ^[1][2]
• Uveal melanoma metastasizes haematogenously, predominantly to the liver.
• Less than 4% of patients with uveal melanoma have detectable metastatic disease, at the time of diagnosis.
• However in further course about half of patients will develop metastases.
• When metastatic disease appears it unavoidably leads to death because of lack of effective systemic treatment.

Complications of eye melanoma include the following:^[3]

• Glaucoma
• Cataract
• Anterior chamber hemorrhage
• Corneal decompensation with edema and band keratopathy
• Metastasis
  • Eye melanoma can spread outside of the eye and to distant areas of the body, including the liver, lungs and bones.
• Vision loss

• Eye melanomas that are large often cause vision loss in the affected eye and may cause complications, such as retinal detachment, that also cause vision loss.
• If small eye melanomas occur in critical parts of the eye they may cause some vision loss.
• There may be difficulty seeing in the center of the vision or on the side.
• Advanced eye melanomas can cause complete vision loss.

• Complications of radiotherapy include the following:^[4]
  • Radiation retinopathy
  • Radiation maculopathy
  • Radiation opticopathy
  • Maculopathy
  • Cataract
  • Neovascular glaucoma
  • Vitreous haemorrhage
  • Retinal detachment and dryness
  • Radiation retinopathy, opticopathy and neovascular glaucoma are responsible for the majority of secondary visual loss and secondary enucleations after therapy.

• The 5-year mortality rate associated with metastasis from ciliary body or choroidal melanoma is approximately 30%, compared with a rate of 2% to 3% for iris melanomas.^[5][6]
• Overall survival depends on tumor size, extraocular spread, and metastases. Even small (<10 mm diameter, <3 mm thickness) tumors still carry a 10-15% 5-year mortality.
• The 10 year-survival for iris melanoma is approximately 95 percent and for ciliochoroidal tumors is 77 percent respectively.
• The tumor node metastasis (TNM) staging system of the American Joint Committee on Cancer takes into account the key factors involved which are known to be of prognostic significance.
• The prognosis is usually poor when local control is not achieved with the initial treatment.^[7][8]
• Detection of circulating tumor cells at the time of diagnosis is an independent risk factor for relapse and shortened survival in patients at high-risk based upon clinical parameters.^[9][10]
• The prognosis for any patient with recurring or relapsing disease is poor, regardless of cell type or stage.

References

1. ↑ Wöll E, Bedikian A, Legha SS (1999). “Uveal melanoma: natural history and treatment options for metastatic disease”. Melanoma Res. 9 (6): 575–81. PMID 10661768.CS1 maint: Multiple names: authors list (link)
2. ↑ Jovanovic P, Mihajlovic M, Djordjevic-Jocic J, Vlajkovic S, Cekic S, Stefanovic V (2013). “Ocular melanoma: an overview of the current status”. Int J Clin Exp Pathol. 6 (7): 1230–44. PMC 3693189. PMID 23826405.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
3. ↑ Singh, Arun D., and Bertil Damato. Clinical ophthalmic oncology : uveal tumors. Heidelberg: Springer, 2014. Print.
4. ↑ Summanen, P; Immonen, I; Kivela, T; Tommila, P; Heikkonen, J; Tarkkanen, A (1996). “Radiation related complications after ruthenium plaque radiotherapy of uveal melanoma”. British Journal of Ophthalmology. 80 (8): 732–739. doi:10.1136/bjo.80.8.732. ISSN 0007-1161.
5. ↑ Shields, CarolL; Mellen, PhoebeL; Morton, SpenserJ (2013). “American joint committee on cancer staging of uveal melanoma”. Oman Journal of Ophthalmology. 6 (2): 116. doi:10.4103/0974-620X.116652. ISSN 0974-620X.
6. ↑ Shields CL, Kaliki S, Furuta M, Fulco E, Alarcon C, Shields JA (2013). “American Joint Committee on Cancer classification of posterior uveal melanoma (tumor size category) predicts prognosis in 7731 patients”. Ophthalmology. 120 (10): 2066–71. doi:10.1016/j.ophtha.2013.03.012. PMID 23664467.CS1 maint: Multiple names: authors list (link)
7. ↑ Egger E, Zografos L, Schalenbourg A, Beati D, Böhringer T, Chamot L; et al. (2003). “Eye retention after proton beam radiotherapy for uveal melanoma”. Int J Radiat Oncol Biol Phys. 55 (4): 867–80. PMID 12605964.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
8. ↑ Egan KM, Ryan LM, Gragoudas ES (1998). “Survival implications of enucleation after definitive radiotherapy for choroidal melanoma: an example of regression on time-dependent covariates”. Arch Ophthalmol. 116 (3): 366–70. PMID 9514491.CS1 maint: Multiple names: authors list (link)
9. ↑ Schuster R, Bechrakis NE, Stroux A, Busse A, Schmittel A, Scheibenbogen C; et al. (2007). “Circulating tumor cells as prognostic factor for distant metastases and survival in patients with primary uveal melanoma”. Clin Cancer Res. 13 (4): 1171–8. doi:10.1158/1078-0432.CCR-06-2329. PMID 17317826.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
10. ↑ Boldin I, Langmann G, Richtig E, Schwantzer G, Ardjomand N, Wegscheider B; et al. (2005). “Five-year results of prognostic value of tyrosinase in peripheral blood of uveal melanoma patients”. Melanoma Res. 15 (6): 503–7. PMID 16314735.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

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