Uveal melanoma (UM) is the most common cause of primary eye cancer in the western world. During embryogenesis neural crest cells migrate to the neural tract where they develop into melanocytes. Melanomas of the uvea are derived from these melanocytes. UM may arise in the iris (5%), ciliary body (23%) or choroid (72%). Choroidal melanomas are the most common and usually display a discoid, dome-shaped or mushroom shaped growth pattern. Approximately 80% of the primary intraocular tumours are diagnosed as UM in patients above the age of 20 years, with a mean age of 60 years (Singh & Topham, 2003). Despite a shift towards more conservative eye treatments, survival has not improved during 1973 to 2008 (Singh et al, 2011). Growth of the primary tumour is related with histopathological features, as well as the genetic changes within these tumours. In this chapter we will not discuss iris melanoma, as this shows a different clinical and genetic behaviour, compared to ciliary body and choroidal melanoma. The clinical features, histopathological profile and genetic alterations of UM, as well as therapeutic options for primary tumours and metastases will be discussed.
The incidence of UM ranges from 4.3 to 10.9 per million (Singh et al, 2009). For the past fifty years, the incidence has remained stable, unlike trends indicating a higher incidence of cutaneous melanoma. The incidence in Europe and United States is comparable to that in Australia and New Zealand. In Europe, a lower incidence is reported in Spain and the south of Italy, about 2 per million, whereas registries in France, the Netherlands, Switzerland and Germany has intermediate values around 4 to 5 per million. The United Kingdom registered over 6 per million, and the highest incidence is up to > 8 per million in Norway and Denmark (Virgili et al, 2007).
3. Predisposing factors
Men and women with UM are more or less affected equally (Damato & Coupland, 2012; Singh et al, 2011). Iris melanoma is more common in women than in men (Damato & Coupland, 2012). Several phenotypes, like blue or grey eyes and fair skin have been suggested to predispose for UM (Schmidt-Pokrzywniak et al, 2009). This might explain why Caucasians are approximately 150 times more frequently affected than Africans (Margo et al, 1998; Singh et al, 2005a). In Asians UM is less common (Biswas et al, 2002).
From all the parts of the uvea the iris is most exposed to ultraviolet light, because of filtering effects of the lens and retinal pigment epithelium (RPE), the choroid receives less light (Singh et al, 2004). Although several epidemiologic and case control studies have been performed to investigate the influence of sunlight exposure on UM, the results are not conclusive (Guenel et al, 2001; Holly et al, 1990; Pane & Hirst, 2000; Shah et al, 2005; Vajdic et al, 2002). UM may occur as a part of familial syndromes, like xeroderma pigmentosa, Li-Fraumeni syndrome and familial breast and ovarian cancer. Of all UM 0.6% is considered to be familial (Singh et al, 1996). In a retrospective study 0.0017% of the primary UM patients were in the setting of familial atypical mole and melanoma syndrome (FAMM). These patients were relatively young with a mean age of 40 years (Singh et al, 1995). Furthermore, an association of neurofibromatosis type 1 and UM has been suggested, since both are of neural crest origin, however this association remains unclear (Honavar et al, 2000). Ocular and oculodermal melanocytosis (Nevus of Ota), dysplastic nevi and cutaneous melanoma are correlated with an increased risk of UM development (Carreno et al, 2012; Gonder et al, 1982; Hammer et al, 1995; Richtig et al, 2004; Singh et al, 1998; Toth-Molnar et al, 2000; van Hees et al, 1994). Additionally, in UM patients ocular and oculodermal melanocytosis are about 35 to 70 times more common (Carreno et al, 2012; Singh et al, 1998).
4. Clinical presentation
Depending on de location and size of the tumour, patients can present with visual complaints. Most UMs are detected during a routine ophthalmic examination. Approximately 30% of the patients have no symptoms at time of diagnosis, and if there are any complaints these consist mostly of blurred vision, floaters, photopsias and visual field loss (Damato, 2010) (figure 1). Usually patients do not present with severe ocular pain, however, this can occur secondary to inflammation or neovascular glaucoma.
Diagnosis of UM is based on a combination of clinical examination with slit lamp biomicroscopy, indirect ophthalmoscopy (figure 1, 2a, 3a) and ultrasonography (US) (figure 2b, 3b). Iris melanomas are readily detectable by slit lamp biomicroscopy, whereas ciliary body tumours are hidden behind the iris and can be visualized by US. Choroidal tumours, depending on their location, are diagnosed by dilated indirect ophthalmoscopy and US. In suspect cases of intravenous fluorescein angiography can be helpful in differentiating melanomas from other diagnoses. Also optical coherence tomography (OCT) and autofluorescence can provide additional information (Lavinsky et al, 2007; Shields et al, 2008). In selected cases, when in doubt, an intraocular biopsy is taken of the tumour.
Indirect ophthalmoscopy through a dilated pupil provides a correct diagnosis in more than 95% of the cases (Char et al, 1980). Accuracy of the right diagnosis is established to be over 99% by experienced clinicians with US, ophthalmoscopy, and fluorescein angiography and confirmed by histopathology (Collaborative Ocular Melanoma Study Group, 1990). The ability to differentiate melanoma from other lesions has improved over the last decades. When comparing studies of 1964 and 1973, in 19% of the enucleated patients with the clinical diagnosis melanoma no histopathological evidence of a melanoma was found (Ferry, 1964; Shields, 1973). The accuracy in diagnosing medium to small sized tumours is quite challenging. Nine percent of presumed melanomas are found to have another diagnosis by fine needle aspiration biopsy (Char & Miller, 1995). Most important is to minimise the delay in referring patients with melanoma to a specialised centre. It is reported that in 29% of the patients a melanoma is missed during the first visit by an ophthalmologist, and that 31.5% of the patients referred to an oncology centre with the diagnosis of melanoma actually had a mimicking lesion (Eskelin & Kivelä, 2002; Khan & Damato, 2007).
Melanoma are generally pigmented, but one fourth are relatively non-pigmented or amelanotic (figure 1). Melanoma can develop into two different directions: towards the vitreous and outwards, through the underlying sclera. Having broken through Bruch’s membrane, into the vitreous, UMs achieve a characteristic shape, even pathognomonic, like a ‘collar button’ or ‘mushroom’. Small melanomas can appear flat or dome shaped.
5.2. Clinical prognostic factor
Well-known clinical prognostic factors are age and location of the tumour. Older patients tend to have a worse prognosis (Shields et al, 2012). One study found that UMs were located predominantly posterior and temporal or had a preference for macular zone, while others found a more equal distribution of melanoma (Krohn et al, 2008; Li et al, 2000; Shields et al, 2009b). Patients with larger tumours, tumours that ruptured through Bruch membrane and in patients who have developed metastasis, the tumours were significantly more often located anterior to the equator (Krohn et al, 2008).
The most important clinical prognostic factor is tumour size, and is often used for selection of the treatment. There are several treatment options, which will be discussed later in this chapter. UM are subdivided into different categories depending on the apical size and diameter, however, many centres use their own definition. Most widely used definition is suggested by the COMS study. Small melanomas are 1.0 - 2.5 mm in apical height and > 5.0 mm in largest basal dimension (Collaborative Ocular Melanoma Study Group, 1997). Medium tumours are defined as tumours 2.5 to 10 mm in apical height and ≤ 16 mm in largest basal diameter. Large tumours are ≥ 2 mm in apical height and > 16 mm in maximal basal diameter, or a melanoma > 10 mm in apical height, regardless of the basal diameter (Collaborative Ocular Melanoma Study Group, 2003). One large study described that each increase in millimeter of tumour thickness increased the risk for metastasis by 5% (Shields et al, 2009b). The mortality rate for small (< 2 - 3 mm height), medium (3 - 8 mm height) and large (> 8 mm height) melanoma was 16%, 32% and 53% in 5 years, respectively, and has not changed in recent years (Diener-West et al, 1992). This supports the model of tumour doubling time of melanoma and its’ related metastasis. The model suggests that micrometastasis already exist several years before diagnosis of the primary tumour (Eskelin et al, 2000). This emphasizes the importance of identifying small melanoma and reducing the risk of metastases.
5.3. Clinical predictive factors of small melanoma
In general, choroidal nevi have a less than 5 mm basal diameter and are minimal in height (< 2 mm), although several definitions of nevi have been proposed. Due to different examination methods and definitions, the prevalence of nevi is between 0.2% and 30% (Gass, 1977; Wilder, 1946). Overall in a Caucasian population the incidence is 6.5% (Sumich et al, 1998). Whenever, growth of a nevus is measured on US in a short time a transformation into a small melanoma is suspected. On the other hand benign nevi can also grow slowly. Mashayekhi
It is important to differentiate melanoma form other choroidal pathologies, such as choroidal nevi, by identifying indicators of potential malignancy which may differentiate nevi from small UM. Shields
Later “Using Helpful Hints Daily” was added to “TFSOM” mnemonic (Shields et al, 2009a). These features indicate a low acoustic profile or Ultrasound Hollowness, absence of a Halo around the tumour and absence of Drusen over the tumour. US hollowness is shown in 25% of nevi that transformed into melanoma, compared to the 4% with growth without US hollowness (Shields et al, 2009a). A halo around a tumour is a pigmented lesion with a surrounding depigmentation, as can also be noticed in dysplastic nevi. Drusen suggest a chronic lesion and usually indicate that the tumour is benign, however this is not conclusive.
5.4. Ancillary testing
US is a non-invasive tool and helps to establish the diagnosis of UM, despite media opacities or whether the tumour is located far peripherally. UM shows characteristic low to medium internal reflectivity on A-scan. B-scan US is primarily used to plan therapy based on the first measurement, and to periodically measure tumour prominence (height) and basal diameter for follow-up. The B-scan can identify possible extraocular extension as an empty area behind the sclera. On B-scan US the internal structure of the tumour is typically seen as a relative homogeneous grey scale, although this pattern is not specifically diagnostic (figure 3b). At the base of the tumour an acoustically silent zone (called acoustic hollowing) is seen, as well as choroidal excavation and shadowing in the orbit (figure 2b). Eighty-eight percent of the UM show US hollowness or low acoustic reflectivity (Boldt et al, 2008). Choroidal excavation is not observed in all melanomas and varies from 42% to 70% (Coleman et al, 1974; Sobottka et al, 1998; Verbeek, 1985). US provides accurate measurements with an interobserver variability of 0.5 mm (Char et al, 1990).
5.4.2. Fluorescein angiography
The diagnostic value of fluorescein angiography in UM is limited. Fluorescein angiography does not show pathognomonic patterns and is especially helpful in differentiating lesions, which simulate melanoma. The pigmentation, size and effect on the RPE of the tumour influence the fluorescein angiogram. It is of little help in some medium to large melanomas that have an intrinsic tumour circulation. This ‘double circulation’ (simultaneous visualization of retinal and choroidal circulation) consists of late staining of the lesion and multiple pin-point leaks at the level of the RPE, which is evident in the early phase of the angiogram. Blockage of background fluorescence and late staining, when fluorescein leaks from the vessels can be seen on an angiogram as well (Atmaca et al, 1999). Characteristic signs are hypofluorescence in the early phase followed by diffuse hyperfluorescence and hyperfluorescent spots (due to changes in RPE). In the late phase the dye accumulates in the tumour tissue and hyperfluorescents (figure 5b). Hypofluorescent spots correspond with deposits of orange pigment on the surface of the tumour.
5.4.3. Indocyanine green angiography
Indocyanine green angiography is designed to visualize the choroidal vessels and provides more information than fluorescein angiography. Whether an evident pattern can be seen on an angiogram depends on the pigmentation, thickness, disruption through Bruch’s membrane and vascularisation of the tumour (Atmaca et al, 1999). More fluorescence is seen in less pigmented and larger tumours. The choroidal vasculature can be better visualised with indocyanine green than fluorescein. On indocyanine green late staining is observed, because of the leaking of indocyanine green in the extracellular space of the tumour (Frenkel et al, 2008; Guyer et al, 1993; Stanga et al, 2003).
5.4.4. Optical coherence tomography and fundus autofluorescence
OCT and fundus autofluorescence imaging have limited use in detecting changes in the choroid, however, both techniques are non-invasive and of help in identifying subtle changes in the RPE, retina and vitreoretinal interface. By means of an OCT subretinal fluid can be visualized and quantified, small tumours can be measured, whereas with fundus autofluorescence orange pigment can be shown. Spectral domain OCT can be useful in the detection of subretinal deposits, vitreous seeding and transretinal tumour extension (Heindl et al, 2009).
Although OCT itself is not useful in diagnosing uveal melanoma, it aids in differentiating other pigmented lesions from melanomas (Schaudig et al, 1998). For example, melanocytoma tend to have a high reflective signal anteriorly, corresponding with the nerve fibre layer, and an optical shadowing posteriorly (Muscat et al, 2001). In most choroidal nevi no characteristic or subtle patterns of autofluorescence were observed (Lavinsky et al, 2007; Shields et al, 2008). Choroidal melanoma and related retinal and RPE changes, show different autofluorescence patterns, and secondary changes, such as subclinical retinal detachments associated with presence of small amounts of subretinal fluid can discriminate small choroidal melanoma and nevi at risk for growth (Muscat et al, 2004). Like some nevi UM show brighter hyperautofluorescence in overlying orange pigment, RPE detachment and subsequently decreased brightness in subretinal fluid and drusen (Shields et al, 2008) (figures 2c and 3c).
5.4.5. Magnetic resonance imaging and computed tomography
Magnetic resonance imaging (MRI) and computed tomography (CT) can be of additional value in the differential diagnosis of UM. On CT an UM appears as a hyperdense lesion with moderate contrast enhancement. Tumours thinner than 2 mm are not detectable on CT. Besides that, CT is less accurate than US in differentiating melanoma and is more expensive (Mafee et al, 1986; Peyster et al, 1985). For extrascleral extension CT is inferior to US (Scott et al, 1998). On the other hand, MRI seems more sensitive and more specific than US for detection of extraocular extension of UM (Hosten et al, 1997). A choroidal melanoma appears hyperintense on a T1 and hypointense on a T2 weighted scan. As this can also be the appearance of a melanocytoma, MRI is not specific for uveal melanoma. Due to the higher expenses of CT and MRI and the superiority of US, both techniques are not routinely used for diagnostic evaluation.
5.5. Differential diagnosis
About 54 different conditions are able to simulate UM. The most frequent diagnosis is choroidal nevus, accounting for 49% of the approximately 1739 presumed melanoma patients referred to a large tertiary Oncology Department in the USA (Shields et al, 2005b). The differentiation between small melanomas and choroidal nevi remains a clinical challenge. Clinical features that are more prevalent in
6. Classification and histopathologic features
UMs develop from melanocytes of the uvea that are derived from neural crest cells. Initially Callender and colleagues described several melanoma cell types, (Callender, 1931) currently three histopathological uveal melanoma categories are being recognised: spindle, epithelioid and mixed cell type (Campbell et al, 1998). Haematoxylin and eosin (H&E) staining is used to differentiate between cell types. Spindle cells exhibit elongated nuclei that may contain eosinophilic nucleoli. In general, Ums containing spindle cells grow slowly and might be associated with better prognosis. On the other hand, UMs consisting of faster growing epithelioid cells, have a more aggressive behaviour, and are therefore associated with poor clinical outcome. Epithelioid cells have more polygonal cytoplasm and contain eccentric placed large pleomorphic nuclei and prominent eosinophilic nucleoli (figure 6). The mixed-cell type melanoma has variable proportion of spindle and epithelioid cells with a minimum of 10% of any one type (Edge & American Joint Committee on Cancer, 2010). Other inter-tumour factors, like the presence of certain extracellular matrix patterns (three closed loops located back to back identified by Periodic-acid Schiff (PAS) staining) and increased mitotic figures (number of mitoses per 50 high-power fields equal to 8mm2) can both provide additional adverse prognostic information (Folberg et al, 1993; Mooy et al, 1995). Other histological features associated with mortality and metastases are mean diameter of ten largest nucleoli, degree of pigmentation, presence of inflammation and tumour necrosis (Gill & Char, 2012). Extrascleral extension by perineural, perivascular, intravascular or direct scleral invasion is correlated with a worse prognosis, especially when the orbital fat resection margin is positive (Collaborative Ocular Melanoma Study Group, 1998).
Immunohistochemistry may be of diagnostic value. S-100 is expressed by cells of neuroectodermal origin. HMB-45 binds to gp100, an antigen expressed by melanocytes that can be useful in differentiating UM from nonmelanocytic tumours (Burnier et al, 1991).
7. Genetic classification
Cytogenetic studies in solid tumours have been a greater challenge than in haematological malignancies since metaphase chromosome spreads of good quality are more difficult to obtain. Solid tumours frequently have highly complex chromosome alterations and are more heterogeneous. Despite this, UM has been well studied since the late eighties with different techniques, such as cytogenetic and fluorescent in situ hybridization (FISH) analysis. Over the years, we have learned that the majority of UMs contain non-random chromosomal anomalies on either the short arm (p) and or long arm (q) of chromosomes 1, 3, 6 and 8, which can serve as prognostic markers.
7.1. Cytogenetic and molecular techniques in UM research
To examine chromosomal changes in UM tissue several cytogenetic and molecular techniques are available. UMs are quite suitable for cytogenetic analysis because of their relatively simply karyotype. Large chromosomal gains, deletions and translocations can be visualized with conventional karyotyping and spectral karyotyping (SKY) (figure 7a). However, for the detection of smaller abnormalities other techniques are necessary, such as FISH (figure 7b), comparative genomic hybridization (CGH) or quantitative polymerase chain reaction (qPCR) based techniques. An approach is the multiplex ligation probe amplification (MLPA) which allows the relative quantification of multiple loci in one single reaction. MLPA can detect patients at risk for metastatic disease using the results for chromosome 3 and 8 with similar accuracy as FISH
After completion of the human genome project, genome-wide DNA assays became available. Micro-assay based CGH, single nucleotide polymorphism (SNP) analysis and gene expression profiling (GEP) analysis are the frequently applied techniques. With the development of Next Generation Sequencing (NGS) technologies, the genome can be analyzed at base pair level. Genome-wide mutation analysis of tumour samples led to the discovery of a subset of genes in UM such as
7.2. Chromosomal anomalies
7.2.1. Monosomy 3
Monosomy of chromosome 3 is observed in approximately 50% of the cases of UM and is strongly associated with clinical and histopathological prognostic factors and with metastatic death (Horsman et al, 1990; Prescher et al, 1990; Sisley et al, 1990). Prescher and associates were the first to find a strong correlation between loss of chromosome 3 and a poor prognosis of the patient (Prescher et al, 1996). Since then several groups have confirmed the prognostic value of monosomy 3 (Kilic et al, 2006; Sisley et al, 2000; Sisley et al, 1997; White et al, 1998). It is assumed that loss of chromosome 3 is a primary event, as it often occurs with other chromosomal aberrations in UM such as 1p loss, and gain of 6p and 8q (Prescher et al, 1995). Kiliç and colleagues established that tumours with concurrent loss of chromosome 1p and 3 are at higher risk of metastasizing than the tumours with other aberrations (Kilic et al, 2005). Mostly one entire copy of chromosome 3 is lost, although in some cases, isodisomy of chromosome 3 is acquired (Aalto et al, 2001; Scholes et al, 2001; White et al, 1998). Partial deletions or translocations have rarely been described on this chromosome making it difficult to map putative tumour suppressor genes. However, recently a mutation in the
7.2.2. Chromosome 8
Abnormalities in chromosome 8, and in particular gain of 8q or an isochromosome 8q, are thought to be a secondary event in UM as variable copy numbers can be present in one melanoma (Horsman & White, 1993; Prescher et al, 1994). Gain of chromosome 8q is frequently found in tumours that also have loss of chromosome 3, and this is associated with a poor patient outcome (Aalto et al, 2001; Prescher et al, 1995; White et al, 1998). A SNP array analysis with this chromosome status is depicted in figure 8. The relationship between the percentages of aberrant copy numbers within UM cells and patient outcome has been investigated. A higher percentage of monosomy 3 and chromosome 8q gain in primary UM cells shows a strong relation with poor disease-free survival compared to low percentage aberrations (van den Bosch et al, 2012).
7.2.3. Chromosome 6
Rearrangements on chromosome 6 affect both arms of the chromosome, resulting in deletions of 6q and gains of 6p. The relative gain of chromosome 6p can occur either through an isochromosome of 6p or a deletion of 6q. Tumours with gain of 6p are thought to be a separate group within UM with an alternative genetic pathway in carcinogenesis, since gain of 6p is frequently found in tumours with disomy 3 (Ehlers et al, 2008; Hoglund et al, 2004; Sisley et al, 1997). However, this combination of gain of 6p with disomy 3 could not be confirmed by others (Mensink et al, 2009). Aberrations resulting in a relative increase of 6p have been found to be related with both a longer survival (White et al, 1998) or a decreased survival (Aalto et al, 2001). The effect of chromosome 6 aberrations on patient outcome is not conclusive.
7.2.4. Chromosome 1
In cutaneous melanoma rearrangements on the short arm of chromosome 1 are a common abnormality, occurring in about 80% of all cases (Fountain et al, 1990; Zhang et al, 1999). In UM this region on 1p is also frequently affected, giving rise to a deletion of 1p. However, these anomalies on chromosome 1 are less common than those in skin melanomas with a frequency of approximately 30% (Horsman & White, 1993; Parrella et al, 1999; Prescher et al, 1990; Prescher et al, 1995; Sisley et al, 2000).
Aberrations on other chromosomes have been explored, such as chromosome 9p21 (Scholes et al, 2001), chromosome 11q23 (Sisley et al, 2000), chromosome 18q22 (Mensink et al, 2008; White et al, 2006), and chromosome 16q (Kilic et al, 2006; Vajdic et al, 2003). The impact on the prognosis, however, remains unclear due to contradictory findings.
7.2.5. Gene expression profiling
Using GEP UMs can be classified into two classes of tumours that correspond remarkably well with the ability of the tumour to metastasize. In a study of 25 UMs, class 1 tumours had a low risk of metastasizing and class 2 tumours had a high risk of developing metastasis (Onken et al, 2004). This molecular classification strongly predicts metastatic death and outperforms other clinical, histopathological and cytogenetic prognostic indicators (Petrausch et al, 2008; van Gils et al, 2008; Worley et al, 2007). Class 1 tumours predominantly show disomy of chromosome 3, whereas class 2 tumours consist mostly of monosomy 3 (Worley et al, 2007).
7.3. Candidate genes
After identifying the non-random chromosomal alterations in UM, the search for potential oncogenes and tumour suppressor genes followed. By narrowing down altered regions on chromosomes, researchers have tried to identify genes involved in tumourigenesis or progression towards metastasis. This way, studies have been conducted on chromosome 8q revealing potential oncogenes such as
Mutations in certain genes have been well described for cutaneous melanoma. Examples of such genes are the oncogenes
7.3.1. The RAS-RAF-MEK-ERK pathway
In a large proportion of the UMs the RAS-RAF-MEK-ERK pathway or mitogen-activated protein kinase (MAPK) pathway is constitutionally activated, leading to excessive cell proliferation and suggesting the presence of activating mutations upstream in the pathway (Weber et al, 2003; Zuidervaart et al, 2005). Mutation analysis on potential mutation sites in the
With the recent discovery of activating
Exome genome sequencing led to the discovery of the BRCA1 associated protein 1 (
Irrespective of primary treatment of the UM nearly half of the patients develop metastases (Gilissen et al, 2011). UM spreads haematogenous, with a high tendency to metastasize to the liver in 90-95% of the patients. One explanation for the development of new distant metastasis years after the control of primary tumour is the presence of circulating tumour cells at time of the initial diagnosis (Manschot et al, 1995). In other words, the disease is often already disseminated at time of tumour diagnosis. Several pathways have been implicated in the preferential homing of tumour cells to the liver, such as hepatocyte growth factor (HGF) and it’s corresponding receptor c-Met, insulin-like growth factor 1 (IGF-1), and chemokine CXCL12 (Bakalian et al, 2008). In case of liver metastasis prognosis is poor with a median survival of approximately 8 months (Eskelin et al, 2003).
Despite the fact that there a no therapeutic options for metastatic UM that improve survival or quality of life, the following methods can be used for screening of liver metastasis: liver function tests (gamma-glutamyl transpeptidase (γGT) and lactate dehydrogenase (LDH) from blood), liver imaging with US, CT and MRI. Although screening annually or semi-annually for liver metastasis by liver function tests are being widely used, there are reports of disseminated liver metastases and normal liver function tests (Donoso et al, 1985; Eskelin et al, 1999).
Patients have 97.5% chance or more of having no metastasis in the case of normal liver function tests, because of the high negative predictive value. However, isolated or combined liver function tests for aspartate aminotransferase (AST), alanine transaminase (ALT), yGT, LDH and phosphatidic acid (PA) are not indicated for detection of early liver metastasis (Mouriaux et al, 2012). Other upcoming screening options make use of serum markers, Among which S-100β (neural crest marker), melanoma inhibitory activity (MIA), tissue polypeptide specific antigen (TPS) and osteopontin (OPN). MIA and S-100β showed significant increase in levels before clinical diagnosis of metastasis (Barak et al, 2011). In a lead time of more than 6 months before clinical metastasis a significant increase in OPN and steeper trendlines in MIA and S-100β levels were demonstrated (Hendler et al, 2011).
9. Treatment of primary UM
Conservation of the eye in UM with useful vision has improved with advances in local irradiation (brachytherapy), heavy particle radiation techniques (proton and helium ion beam), stereotactic radiotherapy (SRT), endoresection, exoresection, transpupillary thermotherapy and photodynamic therapy (Spagnolo et al, 2012). If the tumours are larger, advanced and, in particular, if there is evidence of extraocular extension enucleation is advised (Spagnolo et al, 2012). In addition, enucleation is also performed after serious treatment induced complications (Hungerford, 1993; Shields et al, 1991). Choice of treatment depends on the location and size of the tumour and goals of therapy. Even though enucleation is sometimes required, eye-preserving approaches have shown to be equally successful regarding overall survival and metastasis-free survival (Seddon et al, 1985; Seddon et al, 1990). Brachytherapy is the most common method for treating UM, and currently the ruthenium-106 (Ru-106) and iodine-125 (I-125) applicators are the most frequently used. Brachytherapy can be used in combination with other methods of treatment of UM, such as local resection or transpupillary thermotherapy (Pe'er, 2012). Local control with plaque radiotherapy has provided overall survival comparable to enucleation. Radiation-induced side effects have necessitated secondary enucleation in 10-22% of the patients (Bell & Wilson, 2004; Char et al, 1993; Finger, 1997; Garretson et al, 1987; Gunduz et al, 1999; Lommatzsch et al, 2000; Packer et al, 1992; Shields et al, 1991; Tjho-Heslinga et al, 1999; Vrabec et al, 1991). Local recurrences after brachytherapy are reported between 4 - 28%, depending on the size of the tumour and the follow up time (Damato & Foulds, 1996; Gragoudas, 1997; Karlsson et al, 1989; Seregard et al, 1997; Tjho-Heslinga et al, 1999; Wilson & Hungerford, 1999; Zografos et al, 1992). Radiation-induced complications include radiation retinopathy, radiation maculopathy, radiation opticopathy as well as recurrences (Gragoudas et al, 1999; Kinyoun et al, 1996; Summanen et al, 1996). Heavy particle radiation with positive charged particles (protons or helium-ions) enables treatment of small, medium- and large-choroidal melanomas. The local recurrence rate for proton beam irradiation is similar to brachytherapy and at 10 years is usually around 5% (Gragoudas, 1997; Zografos et al, 1992). Secondary enucleation is performed in 10 - 15% of patients either due to complications or local recurrence. Other complications, such as maculopathy, opticopathy, cataract, glaucoma, vitreous haemorrhage, retinal detachment and dryness have also been described (Desjardins et al, 2012). In concordance with proton beam irradiation radiogenic side effects are also reported after SRT. Side effects, such as radiation retinopathy, opticopathy and neovascular glaucoma are responsible for the majority of secondary visual loss and secondary enucleations after SRT (Mueller et al, 2000; Zehetmayer et al, 2000). The efficacy of SRT for UM has been proven in different studies with local tumour control rates reported over 90%, 5 and 10 years after treatment (Zehetmayer, 2012). Local resection (endoresection and exoresection) of UM aims to conserve the eye and remain a useful vision. The tumour can be removed in several manners, through the vitrous and retinal with a vitreous cutter, endoresection, or through a scleral opening exoresection. Variations of exoresection include iridectomy, iridocyclectomy, cyclochoroidectomy, and choroidectomy. Endoresection as well as exoresection can be used as a primary procedure, after another conservative therapy as a treatment option for recurrences or toxic tumour syndrome. An advantage of local resection is that eyes that would otherwise be inoperable can be preserved, while relative large tumour samples are available for prognostication and research (Damato & Foulds, 1996; Damato, 2012; Robertson, 2001).
10. Treatment of liver metastases
Although treatment options for small to medium sized melanoma improves visual outcome, there has not been any standardized therapy that improves survival in metastatic disease. Systemic treatment options, such as intravenous chemotherapy and immunotherapy do not seem to give promising results or survival benefit (Augsburger et al, 2009). Several locoregional techniques are available, for example immunoembolization, chemoembolization, isolated liver perfusion and hepatic intra-arterial chemotherapy. In highly selected patients, surgical resection of liver metastases can be beneficial. Operating on patients with a time from diagnosis of the primary tumour to liver metastases of > 24 months, ≤ 4 liver metastatic lesions and absence of ‘miliary’ disease (multiple, diffuse, millimetre-sized, dark punctuate lesions on CT) is associated with prolonged survival. A median survival of 27 months has been described in patients with microscopically complete liver resection versus 14 months in patients with microscopically or macroscopically incomplete liver resection (Mariani et al, 2009).
11. Future prospects
With the discovery of
Therapeutically targeting UMs with a
UM: uveal melanoma
RPE: retina pigment epithelia
FAMM: familial atypical mole and melanoma syndrome
OCT: optical coherence tomography
MRI: magnetic resonance imaging
CT: computed tomography
CHRPE: congenital hypertrophy of the retinal pigment epithelium
PEHC: peripheral exudative hemorrhagic chorioretinopathy
H&E: haematoxylin and eosin
PAS: Periodic-acid Schiff
FISH: fluorescent in situ hybridization
SKY: spectral karyotyping
CGH: comparative genomic hybridization
qPCR: quantitative polymerase chain reaction
MLPA: multiplex ligation probe amplification
MAQ: multiplex amplicon quantification
MSA: microsatellite analysis
LOH: loss of heterozygosity
SNP: single nucleotide polymorphism
GEP: gene expression profiling
NGS: next generation sequencing
MAPK: mitogen-activated protein kinase
HGF: hepatocyte growth factor
IGF-1: insulin-like growth factor 1
γGT: gamma-glutamyl transpeptidase
LDH: lactate dehydrogenase
AST: aspartate aminotransferase
ALT : alanine transaminase
PA: phosphatidic acid
MIA: melanoma inhibitory activity
TPS: tissue polypeptide specific antigen
SRT: stereotactic radiotherapy
HDAC: histone deacetylase
Collaborative Ocular Melanoma Study Group (1997). Factors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. Arch Ophthalmol115: 1537-1544.
Collaborative Ocular Melanoma Study Group (1998). Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no. 6. Am J Ophthalmol125: 745-766.
Aalto Y, Eriksson L, Seregard S, Larsson O & Knuutila S (2001) Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1, 6, or 8 in metastasizing primary uveal melanoma. Invest Ophthalmol Vis Sci42: 313-317.
Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN, Boru G, Hovland P & Davidorf FH (2011) Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet48: 856-859.
Abdel-Rahman MH, Yang Y, Zhou XP, Craig EL, Davidorf FH & Eng C (2006) High frequency of submicroscopic hemizygous deletion is a major mechanism of loss of expression of PTEN in uveal melanoma. J Clin Oncol24: 288-295.
Amer R, Pe'er J, Chowers I & Anteby I (2004) Treatment options in the management of choroidal metastases. Ophthalmologica218: 372-377.
Atmaca LS, Batioğlu F & Atmaca P. (1999). Fluorescein and indocyanine green videoangiography of choroidal melanomas. In Jpn J Ophthalmol, Vol. 43. pp. 25-30.
Augsburger JJ, Corrêa ZM & Shaikh AH. (2009). Effectiveness of treatments for metastatic uveal melanoma. In Am J Ophthalmol, Vol. 148. pp. 119-127.
Augsburger JJ, Schroeder RP, Territo C, Gamel JW & Shields JA. (1989). Clinical parameters predictive of enlargement of melanocytic choroidal lesions. In Br J Ophthalmol, Vol. 73. pp. 911-917.
Bakalian S, Marshall JC, Logan P, Faingold D, Maloney S, Di Cesare S, Martins C, Fernandes BF & Burnier MN, Jr. (2008) Molecular pathways mediating liver metastasis in patients with uveal melanoma. Clin Cancer Res14: 951-956.
Barak V, Kaiserman I, Frenkel S, Hendler K, Kalickman I & Pe'er J (2011) The dynamics of serum tumor markers in predicting metastatic uveal melanoma (part 1). Anticancer Res31: 345-349.
Bauer J, Kilic E, Vaarwater J, Bastian BC, Garbe C & de Klein A (2009) Oncogenic GNAQ mutations are not correlated with disease-free survival in uveal melanoma. Br J Cancer101: 813-815.
Bell DJ & Wilson MW (2004) Choroidal melanoma: natural history and management options. Cancer Control11: 296-303.
Biswas J, Krishnakumar S & Shanmugam MP. (2002). Uveal melanoma in Asian Indians: a clinicopathological study. In Arch Ophthalmol, Vol. 120. pp. 522-523.
Boldt HC, Byrne SF, Gilson MM, Finger PT, Green RL, Straatsma BR, Simpson ER & Hawkins BS (2008) Baseline echographic characteristics of tumors in eyes of patients enrolled in the Collaborative Ocular Melanoma Study: COMS report no. 29. Ophthalmology115: 1390-1397, 1397 e1391-1392.
Burnier MN, Jr., McLean IW & Gamel JW (1991) Immunohistochemical evaluation of uveal melanocytic tumors. Expression of HMB-45, S-100 protein, and neuron-specific enolase. Cancer68: 809-814.
Callender GR (1931) Malignant melanotic tumors of the eye: a study of histologic types in 111 cases. Trans Am Acad Ophthalmol Otolaryngol36: 131-142.
Campbell RJ, Sobin LH, Zimmerman LE & World Health Organization. (1998). Histological typing of tumours of the eye and its adnexa. International histological classification of tumours. Springer: Berlin ; London.
Carreno E, Saornil MA, Garcia-Alvarez C, Lopez-Lara F, De Frutos-Baraja JM & Almaraz A (2012) Prevalence of ocular and oculodermal melanocytosis in Spanish population with uveal melanoma. Eye (Lond)26: 159-162.
Char DH, Kroll S, Stone RD, Harrie R & Kerman B. (1990). Ultrasonographic measurement of uveal melanoma thickness: interobserver variability. In Br J Ophthalmol, Vol. 74. pp. 183-185.
Char DH & Miller T. (1995). Accuracy of presumed uveal melanoma diagnosis before alternative therapy. In Br J Ophthalmol, Vol. 79. pp. 692-696.
Char DH, Quivey JM, Castro JR, Kroll S & Phillips T (1993) Helium ions versus iodine 125 brachytherapy in the management of uveal melanoma. A prospective, randomized, dynamically balanced trial. Ophthalmology100: 1547-1554.
Char DH, Stone RD, Irvine AR, Crawford JB, Hilton GF, Lonn LI & Schwartz A (1980) Diagnostic modalities in choroidal melanoma. Am J Ophthalmol89: 223-230.
Cohen Y, Goldenberg-Cohen N, Parrella P, Chowers I, Merbs SL, Pe'er J & Sidransky D (2003) Lack of BRAF mutation in primary uveal melanoma. Invest Ophthalmol Vis Sci44: 2876-2878.
Coleman DJ, Abramson DH, Jack RL & Franzen LA (1974) Ultrasonic diagnosis of tumors of the choroid. Arch Ophthalmol91: 344-354.
Collaborative Ocular Melanoma Study Group (2003) Comparison of clinical, echographic, and histopathological measurements from eyes with medium-sized choroidal melanoma in the collaborative ocular melanoma study: COMS report no. 21. Arch Ophthalmol121: 1163-1171.
Damato B (2010) Does ocular treatment of uveal melanoma influence survival? Br J Cancer103: 285-290.
Damato B, Dopierala J, Klaasen A, van Dijk M, Sibbring J & Coupland SE (2009) Multiplex ligation-dependent probe amplification of uveal melanoma: correlation with metastatic death. Invest Ophthalmol Vis Sci50: 3048-3055.
Damato B & Foulds WS (1996) Indications for trans-scleral local resection of uveal melanoma. Br J Ophthalmol80: 1029-1030.
Damato BE (2012) Local resection of uveal melanoma. Dev Ophthalmol49: 66-80.
Damato BE & Coupland SE (2012) Differences in uveal melanomas between men and women from the British Isles. Eye (Lond)26: 292-299.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR & Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature417: 949-954.
Demirci H, Shields CL, Chao A-N & Shields JA. (2003). Uveal metastasis from breast cancer in 264 patients. In Am J Ophthalmol, Vol. 136. pp. 264-271.
Desjardins L, Lumbroso-Le Rouic L, Levy-Gabriel C, Cassoux N, Dendale R, Mazal A, Delacroix S, Sastre X, Plancher C & Asselain B (2012) Treatment of uveal melanoma by accelerated proton beam. Dev Ophthalmol49: 41-57.
Diener-West M, Hawkins BS, Markowitz JA & Schachat AP. (1992). A review of mortality from choroidal melanoma. II. A meta-analysis of 5-year mortality rates following enucleation, 1966 through 1988. In Arch Ophthalmol, Vol. 110. pp. 245-250.
Donoso LA, Shields JA, Augsburger JJ, Orth DH & Johnson P (1985) Metastatic uveal melanoma: diffuse hepatic metastasis in a patient with concurrent normal serum liver enzyme levels and liver scan. Arch Ophthalmol103: 758.
Edge SB & American Joint Committee on Cancer. (2010). AJCC cancer staging manual. Springer: New York ; London.
Ehlers JP & Harbour JW (2005) NBS1 expression as a prognostic marker in uveal melanoma. Clin Cancer Res11: 1849-1853.
Ehlers JP, Worley L, Onken MD & Harbour JW (2005) DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma. Clin Cancer Res11: 3609-3613.
Ehlers JP, Worley L, Onken MD & Harbour JW (2008) Integrative genomic analysis of aneuploidy in uveal melanoma. Clin Cancer Res14: 115-122.
Eskelin S & Kivelä T. (2002). Mode of presentation and time to treatment of uveal melanoma in Finland. In Br J Ophthalmol, Vol. 86. pp. 333-338.
Eskelin S, Pyrhonen S, Hahka-Kemppinen M, Tuomaala S & Kivela T (2003) A prognostic model and staging for metastatic uveal melanoma. Cancer97: 465-475.
Eskelin S, Pyrhönen S, Summanen P, Hahka-Kemppinen M & Kivelä T. (2000). Tumor doubling times in metastatic malignant melanoma of the uvea: tumor progression before and after treatment. In Ophthalmology, Vol. 107. pp. 1443-1449.
Eskelin S, Pyrhonen S, Summanen P, Prause JU & Kivela T (1999) Screening for metastatic malignant melanoma of the uvea revisited. Cancer85: 1151-1159.
Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC & Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature434: 917-921.
Ferry AP (1964) Lesions Mistaken for Malignant Melanoma of the Posterior Uvea. A Clinicopathologic Analysis of 100 Cases with Ophthalmoscopically Visible Lesions. Arch Ophthalmol72: 463-469.
Finger PT (1997) Radiation therapy for choroidal melanoma. Surv Ophthalmol42: 215-232.
Folberg R, Rummelt V, Parys-Van Ginderdeuren R, Hwang T, Woolson RF, Pe'er J & Gruman LM (1993) The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology100: 1389-1398.
Fountain JW, Bale SJ, Housman DE & Dracopoli NC (1990) Genetics of melanoma. Cancer Surv9: 645-671.
Frenkel S, Barzel I, Levy J, Lin AY, Bartsch DU, Majumdar D, Folberg R & Pe'er J (2008) Demonstrating circulation in vasculogenic mimicry patterns of uveal melanoma by confocal indocyanine green angiography. Eye (Lond)22: 948-952.
Garretson BR, Robertson DM & Earle JD (1987) Choroidal melanoma treatment with iodine 125 brachytherapy. Arch Ophthalmol105: 1394-1397.
Gass JD (1977) Problems in the differential diagnosis of choroidal nevi and malignant melanomas. The XXXIII Edward Jackson Memorial Lecture. Am J Ophthalmol83: 299-323.
Gilissen C, Hoischen A, Brunner HG & Veltman JA (2011) Unlocking Mendelian disease using exome sequencing. Genome Biol12: 228.
Gill HS & Char DH (2012) Uveal melanoma prognostication: from lesion size and cell type to molecular class. Can J Ophthalmol47: 246-253.
Gonder JR, Shields JA, Albert DM, Augsburger JJ & Lavin PT (1982) Uveal malignant melanoma associated with ocular and oculodermal melanocytosis. Ophthalmology89: 953-960.
Gragoudas ES (1997) 1996 Jules Gonin Lecture of the Retina Research Foundation. Long-term results after proton irradiation of uveal melanomas. Graefes Arch Clin Exp Ophthalmol235: 265-267.
Gragoudas ES, Li W, Lane AM, Munzenrider J & Egan KM (1999) Risk factors for radiation maculopathy and papillopathy after intraocular irradiation. Ophthalmology106: 1571-1577; discussion 1577-1578.
Collaborative Ocular Melanoma Study Group (1990). Accuracy of diagnosis of choroidal melanomas in the Collaborative Ocular Melanoma Study. COMS report no. 1. In Arch Ophthalmol, Vol. 108. pp. 1268-1273.
Guenel P, Laforest L, Cyr D, Fevotte J, Sabroe S, Dufour C, Lutz JM & Lynge E (2001) Occupational risk factors, ultraviolet radiation, and ocular melanoma: a case-control study in France. Cancer Causes Control12: 451-459.
Gunduz K, Shields CL, Shields JA, Cater J, Freire JE & Brady LW (1999) Radiation complications and tumor control after plaque radiotherapy of choroidal melanoma with macular involvement. Am J Ophthalmol127: 579-589.
Guyer DR, Yannuzzi LA, Krupsky S, Slakter JS, Sorenson JA, Orlock D, Friedman E & Gragoudas ES (1993) Digital indocyanine-green videoangiography of intraocular tumors. Semin Ophthalmol8: 224-229.
Hammer H, Tóth-Molńar E, Oláh J & Dobozy A. (1995). Cutaneous dysplastic naevi: risk factor for uveal melanoma. In Lancet, Vol. 346. pp. 255-256.
Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C & Bowcock AM (2010) Frequent mutation of BAP1 in metastasizing uveal melanomas. Science330: 1410-1413.
Heindl LM, Mardin CY, Holbach LM, Naumann GO, Kruse FE & Knorr HL (2009) Vitreal seeding from uveal melanoma detected by high-resolution spectral-domain optical coherence tomography. Arch Ophthalmol127: 1062-1064.
Hendler K, Pe'er J, Kaiserman I, Baruch R, Kalickman I, Barak V & Frenkel S (2011) Trends in liver function tests: a comparison with serum tumor markers in metastatic uveal melanoma (part 2). Anticancer Res31: 351-357.
Hoglund M, Gisselsson D, Hansen GB, White VA, Sall T, Mitelman F & Horsman D (2004) Dissecting karyotypic patterns in malignant melanomas: temporal clustering of losses and gains in melanoma karyotypic evolution. Int J Cancer108: 57-65.
Holly EA, Aston DA, Char DH, Kristiansen JJ & Ahn DK. (1990). Uveal melanoma in relation to ultraviolet light exposure and host factors. In Cancer Res., Vol. 50. pp. 5773-5777.
Honavar SG, Singh AD, Shields CL, Shields JA & Eagle RC. (2000). Iris melanoma in a patient with neurofibromatosis. In Surv Ophthalmol, Vol. 45. pp. 231-236.
Horsman DE, Sroka H, Rootman J & White VA (1990) Monosomy 3 and isochromosome 8q in a uveal melanoma. Cancer Genet Cytogenet45: 249-253.
Horsman DE & White VA (1993) Cytogenetic analysis of uveal melanoma. Consistent occurrence of monosomy 3 and trisomy 8q. Cancer71: 811-819.
Hosten N, Bornfeld N, Wassmuth R, Lemke AJ, Sander B, Bechrakis NE & Felix R (1997) Uveal melanoma: detection of extraocular growth with MR imaging and US. Radiology202: 61-67.
Hungerford JL (1993) Surgical treatment of ocular melanoma. Melanoma Res3: 305-312.
Ibrahim N & Haluska FG (2009) Molecular pathogenesis of cutaneous melanocytic neoplasms. Annu Rev Pathol4: 551-579.
Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, Minna J, Borodovsky A, Schultz DC, Wilkinson KD, Maul GG, Barlev N, Berger SL, Prendergast GC & Rauscher FJ, 3rd (1998) BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene16: 1097-1112.
Kanthan GL, Jayamohan J, Yip D & Conway RM. (2007). Management of metastatic carcinoma of the uveal tract: an evidence-based analysis. In Clin Experiment Ophthalmol, Vol. 35. pp. 553-565.
Karlsson UL, Augsburger JJ, Shields JA, Markoe AM, Brady LW & Woodleigh R (1989) Recurrence of posterior uveal melanoma after 60Co episcleral plaque therapy. Ophthalmology96: 382-388.
Khalili JS, Yu X, Wang J, Hayes BC, Davies MA, Lizee G, Esmaeli B & Woodman SE (2012) Combination Small Molecule MEK and PI3K Inhibition Enhances Uveal Melanoma Cell Death in a Mutant GNAQ- and GNA11-Dependent Manner. Clin Cancer Res18: 4345-4355.
Khan J & Damato BE (2007) Accuracy of choroidal melanoma diagnosis by general ophthalmologists: a prospective study. Eye (Lond)21: 595-597.
Kilic E, Bruggenwirth HT, Verbiest MM, Zwarthoff EC, Mooy NM, Luyten GP & de Klein A (2004) The RAS-BRAF kinase pathway is not involved in uveal melanoma. Melanoma Res14: 203-205.
Kilic E, Naus NC, van Gils W, Klaver CC, van Til ME, Verbiest MM, Stijnen T, Mooy CM, Paridaens D, Beverloo HB, Luyten GP & de Klein A (2005) Concurrent loss of chromosome arm 1p and chromosome 3 predicts a decreased disease-free survival in uveal melanoma patients. Invest Ophthalmol Vis Sci46: 2253-2257.
Kilic E, van Gils W, Lodder E, Beverloo HB, van Til ME, Mooy CM, Paridaens D, de Klein A & Luyten GP (2006) Clinical and cytogenetic analyses in uveal melanoma. Invest Ophthalmol Vis Sci47: 3703-3707.
Kinyoun JL, Lawrence BS & Barlow WE (1996) Proliferative radiation retinopathy. Arch Ophthalmol114: 1097-1100.
Krohn J, Froystein T & Dahl O. (2008). Posterior uveal melanoma. Distribution of the sites of origin and patterns of tumour extent in the ocular fundus. In Br J Ophthalmol, Vol. 92. pp. 751-756.
Kumps C, Van Roy N, Heyrman L, Goossens D, Del-Favero J, Noguera R, Vandesompele J, Speleman F & De Preter K (2010) Multiplex Amplicon Quantification (MAQ), a fast and efficient method for the simultaneous detection of copy number alterations in neuroblastoma. BMC Genomics11: 298.
Landreville S, Agapova OA, Matatall KA, Kneass ZT, Onken MD, Lee RS, Bowcock AM & Harbour JW (2012) Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma. Clin Cancer Res18: 408-416.
Lavinsky D, Belfort RN, Navajas E, Torres V, Martins MC & Belfort R, Jr. (2007) Fundus autofluorescence of choroidal nevus and melanoma. Br J Ophthalmol91: 1299-1302.
Lee CS, Bae JH, Jeon IH, Byeon SH, Koh HJ & Lee SC. (2010). Melanocytoma of the optic disk in the Korean population. In Retina (Philadelphia, Pa), Vol. 30. pp. 1714-1720.
Li W, Judge H, Gragoudas ES, Seddon JM & Egan KM. (2000). Patterns of tumor initiation in choroidal melanoma. In Cancer Res., Vol. 60. pp. 3757-3760.
Lommatzsch PK, Werschnik C & Schuster E (2000) Long-term follow-up of Ru-106/Rh-106 brachytherapy for posterior uveal melanoma. Graefes Arch Clin Exp Ophthalmol238: 129-137.
Mafee MF, Peyman GA, Grisolano JE, Fletcher ME, Spigos DG, Wehrli FW, Rasouli F & Capek V (1986) Malignant uveal melanoma and simulating lesions: MR imaging evaluation. Radiology160: 773-780.
Manschot WA, Lee WR & van Strik R (1995) Uveal melanoma: updated considerations on current management modalities. Int Ophthalmol19: 203-209.
Mantel I, Uffer S & Zografos L (2009) Peripheral exudative hemorrhagic chorioretinopathy: a clinical, angiographic, and histologic study. Am J Ophthalmol148: 932-938 e931.
Margo CE, Mulla Z & Billiris K. (1998). Incidence of surgically treated uveal melanoma by race and ethnicity. In Ophthalmology, Vol. 105. pp. 1087-1090.
Mariani P, Piperno-Neumann S, Servois V, Berry MG, Dorval T, Plancher C, Couturier J, Levy-Gabriel C, Lumbroso-Le Rouic L, Desjardins L & Salmon RJ (2009) Surgical management of liver metastases from uveal melanoma: 16 years' experience at the Institut Curie. Eur J Surg Oncol35: 1192-1197.
Mashayekhi A, Siu S, Shields CL & Shields JA (2011) Slow enlargement of choroidal nevi: a long-term follow-up study. Ophthalmology118: 382-388.
McCluskey PJ, Watson PG, Lightman S, Haybittle J, Restori M & Branley M. (1999). Posterior scleritis: clinical features, systemic associations, and outcome in a large series of patients. In Ophthalmology, Vol. 106. pp. 2380-2386.
Mensink HW, Kilic E, Vaarwater J, Douben H, Paridaens D & de Klein A (2008) Molecular cytogenetic analysis of archival uveal melanoma with known clinical outcome. Cancer Genet Cytogenet181: 108-111.
Mensink HW, Vaarwater J, Kilic E, Naus NC, Mooy N, Luyten G, Bruggenwirth HT, Paridaens D & de Klein A (2009) Chromosome 3 intratumor heterogeneity in uveal melanoma. Invest Ophthalmol Vis Sci50: 500-504.
Meyer D, Ge J, Blinder KJ, Sinard J & Xu S. (1999). Malignant transformation of an optic disk melanocytoma. In Am J Ophthalmol, Vol. 127. pp. 710-714.
Mooy CM, Luyten GP, de Jong PT, Luider TM, Stijnen T, van de Ham F, van Vroonhoven CC & Bosman FT (1995) Immunohistochemical and prognostic analysis of apoptosis and proliferation in uveal melanoma. Am J Pathol147: 1097-1104.
Mooy CM, Van der Helm MJ, Van der Kwast TH, De Jong PT, Ruiter DJ & Zwarthoff EC (1991) No N-ras mutations in human uveal melanoma: the role of ultraviolet light revisited. Br J Cancer64: 411-413.
Mouriaux F, Diorio C, Bergeron D, Berchi C & Rousseau A (2012) Liver function testing is not helpful for early diagnosis of metastatic uveal melanoma. Ophthalmology119: 1590-1595.
Mueller AJ, Talies S, Schaller UC, Hoops JP, Schriever S, Kampik A, Wowra B, Horstmann G & Mack A (2000) [Stereotaxic precision irradiation of large uveal melanomas with the gamma knife]
Die stereotaktische Prazisionsbestrahlung grosser uvealer Melanome mit dem Gamma-Knife. Ophthalmologe97: 537-545.
Muscat S, Parks S, Kemp E & Keating D (2004) Secondary retinal changes associated with choroidal naevi and melanomas documented by optical coherence tomography. Br J Ophthalmol88: 120-124.
Muscat S, Srinivasan S, Sampat V, Kemp E, Parks S & Keating D (2001) Optical coherence tomography in the diagnosis of subclinical serous detachment of the macula secondary to a choroidal nevus. Ophthalmic Surg Lasers32: 474-476.
Nakamura S, Hikita, Yamakawa, Moriya, Yano, Furusato, Cameron & Rushing. (2012). A clinically challenging diagnosis of adenoma of the retinal pigment epithelium presenting with clinical features of choroidal hemangioma. In OPTHpp. 497.
Naus NC, Zuidervaart W, Rayman N, Slater R, van Drunen E, Ksander B, Luyten GP & Klein A (2000) Mutation analysis of the PTEN gene in uveal melanoma cell lines. Int J Cancer87: 151-153.
Onken MD, Worley LA, Ehlers JP & Harbour JW (2004) Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res64: 7205-7209.
Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM & Harbour JW (2008) Oncogenic mutations in GNAQ occur early in uveal melanoma. Invest Ophthalmol Vis Sci49: 5230-5234.
Packer S, Stoller S, Lesser ML, Mandel FS & Finger PT (1992) Long-term results of iodine 125 irradiation of uveal melanoma. Ophthalmology99: 767-773; discussion 774.
Pane AR & Hirst LW (2000) Ultraviolet light exposure as a risk factor for ocular melanoma in Queensland, Australia. Ophthalmic Epidemiol7: 159-167.
Parrella P, Caballero OL, Sidransky D & Merbs SL (2001) Detection of c-myc amplification in uveal melanoma by fluorescent in situ hybridization. Invest Ophthalmol Vis Sci42: 1679-1684.
Parrella P, Sidransky D & Merbs SL (1999) Allelotype of posterior uveal melanoma: implications for a bifurcated tumor progression pathway. Cancer Res59: 3032-3037.
Pe'er J (2012) Ruthenium-106 brachytherapy. Dev Ophthalmol49: 27-40.
Petrausch U, Martus P, Tonnies H, Bechrakis NE, Lenze D, Wansel S, Hummel M, Bornfeld N, Thiel E, Foerster MH & Keilholz U (2008) Significance of gene expression analysis in uveal melanoma in comparison to standard risk factors for risk assessment of subsequent metastases. Eye (Lond)22: 997-1007.
Peyster RG, Augsburger JJ, Shields JA, Satchell TV, Markoe AM, Clarke K & Haskin ME (1985) Choroidal melanoma: comparison of CT, fundoscopy, and US. Radiology156: 675-680.
Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM & Meltzer PS (2003) High frequency of BRAF mutations in nevi. Nat Genet33: 19-20.
Prescher G, Bornfeld N & Becher R (1990) Nonrandom chromosomal abnormalities in primary uveal melanoma. J Natl Cancer Inst82: 1765-1769.
Prescher G, Bornfeld N & Becher R (1994) Two subclones in a case of uveal melanoma. Relevance of monosomy 3 and multiplication of chromosome 8q. Cancer Genet Cytogenet77: 144-146.
Prescher G, Bornfeld N, Friedrichs W, Seeber S & Becher R (1995) Cytogenetics of twelve cases of uveal melanoma and patterns of nonrandom anomalies and isochromosome formation. Cancer Genet Cytogenet80: 40-46.
Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jockel KH & Becher R (1996) Prognostic implications of monosomy 3 in uveal melanoma. Lancet347: 1222-1225.
Ratanatharathorn V, Powers WE, Grimm J, Steverson N, Han I, Ahmad K & Lattin PB (1991) Eye metastasis from carcinoma of the breast: diagnosis, radiation treatment and results. Cancer Treat Rev18: 261-276.
Richter MN, Bechrakis NE, Stoltenburg-Didinger G & Foerster MH. (2003). Transscleral resection of a ciliary body leiomyoma in a child: case report and review of the literature. In Graefes Arch Clin Exp Ophthalmol, Vol. 241. pp. 953-957.
Richtig E, Langmann G, M uuml llner K & Smolle J. (2004). Ocular Melanoma: Epidemiology, Clinical Presentation and Relationship with Dysplastic Nevi. In Neuropsychobiology, Vol. 218. pp. 111-114.
Robertson DM (2001) Melanoma endoresection: a perspective. Retina21: 403-407.
Ross JJ & Kemp EG (2009) Large choroidal osteoma with macular decalcification. Retina29: 413-414.
Rosset A, Zografos L, Coucke P, Monney M & Mirimanoff RO (1998) Radiotherapy of choroidal metastases. Radiother Oncol46: 263-268.
Rottinger EM, Heckemann R, Scherer E, Vogel M & Meyer-Schwickerath G (1976) Radiation therapy of choroidal metastases from breast cancer. Albrecht Von Graefes Arch Klin Exp Ophthalmol200: 243-250.
Saldanha G, Purnell D, Fletcher A, Potter L, Gillies A & Pringle JH (2004) High BRAF mutation frequency does not characterize all melanocytic tumor types. Int J Cancer111: 705-710.
Schaudig U, Hassenstein A, Bernd A, Walter A & Richard G (1998) Limitations of imaging choroidal tumors in vivo by optical coherence tomography. Graefes Arch Clin Exp Ophthalmol236: 588-592.
Schmidt-Pokrzywniak A, Jöckel K-H, Bornfeld N, Sauerwein W & Stang A. (2009). Positive interaction between light iris color and ultraviolet radiation in relation to the risk of uveal melanoma: a case-control study. In Ophthalmology, Vol. 116. pp. 340-348.
Scholes AG, Liloglou T, Maloney P, Hagan S, Nunn J, Hiscott P, Damato BE, Grierson I & Field JK (2001) Loss of heterozygosity on chromosomes 3, 9, 13, and 17, including the retinoblastoma locus, in uveal melanoma. Invest Ophthalmol Vis Sci42: 2472-2477.
Scott IU, Murray TG & Hughes JR (1998) Evaluation of imaging techniques for detection of extraocular extension of choroidal melanoma. Arch Ophthalmol116: 897-899.
Seddon JM, Gragoudas ES, Albert DM, Hsieh CC, Polivogianis L & Friedenberg GR (1985) Comparison of survival rates for patients with uveal melanoma after treatment with proton beam irradiation or enucleation. Am J Ophthalmol99: 282-290.
Seddon JM, Gragoudas ES, Egan KM, Glynn RJ, Howard S, Fante RG & Albert DM (1990) Relative survival rates after alternative therapies for uveal melanoma. Ophthalmology97: 769-777.
Seregard S, aft Trampe E, Lax I, Kock E & Lundell G (1997) Results following episcleral ruthenium plaque radiotherapy for posterior uveal melanoma. The Swedish experience. Acta Ophthalmol Scand75: 11-16.
Shah CP, Weis E, Lajous M, Shields JA & Shields CL. (2005). Intermittent and Chronic Ultraviolet Light Exposure and Uveal Melanoma. In Ophthalmology, Vol. 112. pp. 1599-1607.
Shields CL, Bianciotto C, Pirondini C, Materin MA, Harmon SA & Shields JA. (2008). Autofluorescence of choroidal melanoma in 51 cases. In Br J Ophthalmol, Vol. 92. pp. 617-622.
Shields CL, Cater J, Shields JA, Singh AD, Santos MC & Carvalho C (2000) Combination of clinical factors predictive of growth of small choroidal melanocytic tumors. Arch Ophthalmol118: 360-364.
Shields CL, Furuta M, Berman EL, Zahler JD, Hoberman DM, Dinh DH, Mashayekhi A & Shields JA (2009a) Choroidal nevus transformation into melanoma: analysis of 2514 consecutive cases. Arch Ophthalmol127: 981-987.
Shields CL, Furuta M, Thangappan A, Nagori S, Mashayekhi A, Lally DR, Kelly CC, Rudich DS, Nagori AV, Wakade OA, Mehta S, Forte L, Long A, Dellacava EF, Kaplan B & Shields JA. (2009b). Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. In Arch Ophthalmol, Vol. 127. pp. 989-998.
Shields CL, Kaliki S, Furuta M, Mashayekhi A & Shields JA (2012) Clinical spectrum and prognosis of uveal melanoma based on age at presentation in 8,033 cases. Retina32: 1363-1372.
Shields CL, Salazar PF, Mashayekhi A & Shields JA. (2009c). Peripheral Exudative Hemorrhagic Chorioretinopathy Simulating Choroidal Melanoma in 173 Eyes. In Ophthalmology, Vol. 116. pp. 529-535. American Academy of Ophthalmology.
Shields CL, Salazar PF, Mashayekhi A & Shields JA (2009d) Peripheral exudative hemorrhagic chorioretinopathy simulating choroidal melanoma in 173 eyes. Ophthalmology116: 529-535.
Shields CL, Shields JA, Gross NE, Schwartz GP & Lally SE (1997) Survey of 520 eyes with uveal metastases. Ophthalmology104: 1265-1276.
Shields CL, Shields JA, Kiratli H, De Potter P & Cater JR. (1995). Risk factors for growth and metastasis of small choroidal melanocytic lesions. In Trans Am Ophthalmol Soc, Vol. 93. pp. 259-275- discussion 275-259.
Shields CL, Sun H, Demirci H & Shields JA. (2005a). Factors predictive of tumor growth, tumor decalcification, choroidal neovascularization, and visual outcome in 74 eyes with choroidal osteoma. In Arch Ophthalmol, Vol. 123. pp. 1658-1666.
Shields JA. (1973). Lesions simulating malignant melanoma of the posterior uvea. In Arch Ophthalmol, Vol. 89. pp. 466-471.
Shields JA, Demirci H, Mashayekhi A, Eagle Jr. RC & Shields CL. (2006). Melanocytoma of the optic disk: a review. In Surv Ophthalmol, Vol. 51. pp. 93-104.
Shields JA, Demirci H, Mashayekhi A & Shields CL. (2004). Melanocytoma of optic disc in 115 cases. In Ophthalmology, Vol. 111. pp. 1739-1746.
Shields JA, Eagle RC, Shields CL, Brown GC & Lally SE. (2009e). Malignant Transformation of Congenital Hypertrophy of the Retinal Pigment Epithelium. In OPHTHA, Vol. 116. pp. 2213-2216. Elsevier Inc.
Shields JA, Mashayekhi A, Ra S & Shields CL (2005b) Pseudomelanomas of the posterior uveal tract: the 2006 Taylor R. Smith Lecture. Retina25: 767-771.
Shields JA, Shields CL & Donoso LA (1991) Management of posterior uveal melanoma. Surv Ophthalmol36: 161-195.
Shields JA, Shields CL, Eagle RC & De Potter P. (1994). Observations on seven cases of intraocular leiomyoma. The 1993 Byron Demorest Lecture. In Arch Ophthalmol, Vol. 112. pp. 521-528.
Singh AD, Bergman L & Seregard S. (2005a). Uveal melanoma: epidemiologic aspects. In Ophthalmol Clin North Am, Vol. 18. pp. 75-84- viii.
Singh AD, Damato BE, Pe'er J, Murphee AL & Perry JD. (2009). Essentials of Ophthalmic Oncology pp. 288. Slack Incorporated.
Singh AD, De Potter P, Fijal BA, Shields CL, Shields JA & Elston RC (1998) Lifetime prevalence of uveal melanoma in white patients with oculo(dermal) melanocytosis. Ophthalmology105: 195-198.
Singh AD, Kalyani P & Topham A (2005b) Estimating the risk of malignant transformation of a choroidal nevus. Ophthalmology112: 1784-1789.
Singh AD, Rennie IG, Seregard S, Giblin M & McKenzie J. (2004). Sunlight exposure and pathogenesis of uveal melanoma. In Surv Ophthalmol, Vol. 49. pp. 419-428.
Singh AD, Shields CL, De Potter P, Shields JA, Trock B, Cater J & Pastore D. (1996). Familial uveal melanoma. Clinical observations on 56 patients. In Arch Ophthalmol, Vol. 114. pp. 392-399.
Singh AD, Shields CL, Shields JA, Eagle RC & De Potter P. (1995). Uveal melanoma and familial atypical mole and melanoma (FAM-M) syndrome. In Ophthalmic Genet., Vol. 16. pp. 53-61.
Singh AD & Topham A (2003) Incidence of uveal melanoma in the United States: 1973-1997. Ophthalmology110: 956-961.
Singh AD, Turell ME & Topham AK. (2011). Uveal Melanoma: Trends in Incidence, Treatment, and Survival. In Ophthalmology, Vol. 118. pp. 1881-1885. Elsevier Inc.
Singh N, Kulkarni P, Aggarwal AN, Mittal BR, Gupta N, Behera D & Gupta A. (2012). Choroidal Metastasis as a Presenting Manifestation of Lung Cancer. In Medicine, Vol. 91. pp. 179-194.
Sisley K, Parsons MA, Garnham J, Potter AM, Curtis D, Rees RC & Rennie IG (2000) Association of specific chromosome alterations with tumour phenotype in posterior uveal melanoma. Br J Cancer82: 330-338.
Sisley K, Rennie IG, Cottam DW, Potter AM, Potter CW & Rees RC (1990) Cytogenetic findings in six posterior uveal melanomas: involvement of chromosomes 3, 6, and 8. Genes Chromosomes Cancer2: 205-209.
Sisley K, Rennie IG, Parsons MA, Jacques R, Hammond DW, Bell SM, Potter AM & Rees RC (1997) Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer19: 22-28.
Sobottka B, Schlote T, Krumpaszky HG & Kreissig I. (1998). Choroidal metastases and choroidal melanomas: comparison of ultrasonographic findings. In Br J Ophthalmol, Vol. 82. pp. 159-161.
Spagnolo F, Caltabiano G & Queirolo P. (2012). Uveal melanoma. In Cancer Treatment Reviews, Vol. 38. pp. 549-553. Elsevier Ltd.
Stanga PE, Lim JI & Hamilton P (2003) Indocyanine green angiography in chorioretinal diseases: indications and interpretation: an evidence-based update. Ophthalmology110: 15-21; quiz 22-13.
Sumich P, Mitchell P & Wang JJ. (1998). Choroidal nevi in a white population: the Blue Mountains Eye Study. In Arch Ophthalmol, Vol. 116. pp. 645-650.
Summanen P, Immonen I, Kivela T, Tommila P, Heikkonen J & Tarkkanen A (1996) Radiation related complications after ruthenium plaque radiotherapy of uveal melanoma. Br J Ophthalmol80: 732-739.
Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H & Carbone M (2011) Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet43: 1022-1025.
Thibodeau SN, Bren G & Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science260: 816-819.
Tjho-Heslinga RE, Davelaar J, Kemme HM, de Vroome H, Oosterhuis JA, Bleeker JC & Leer JW (1999) Results of ruthenium irradiation of uveal melanomas: the Dutch experience. Radiother Oncol53: 133-137.
Toth-Molnar E, Hammer H & Olah J (2000) Cutaneous dysplastic naevi in uveal melanoma patients: markers for prognosis? Melanoma Res10: 36-39.
Tsina EK, Lane AM, Zacks DN, Munzenrider JE, Collier JM & Gragoudas ES (2005) Treatment of metastatic tumors of the choroid with proton beam irradiation. Ophthalmology112: 337-343.
Vaarwater J, van den Bosch T, Mensink HW, van Kempen C, Verdijk RM, Naus NC, Paridaens D, Bruggenwirth HT, Kilic E & de Klein A (2012) Multiplex ligation-dependent probe amplification equals fluorescence in-situ hybridization for the identification of patients at risk for metastatic disease in uveal melanoma. Melanoma Res22: 30-37.
Vajdic CM, Hutchins AM, Kricker A, Aitken JF, Armstrong BK, Hayward NK & Armes JE (2003) Chromosomal gains and losses in ocular melanoma detected by comparative genomic hybridization in an Australian population-based study. Cancer Genet Cytogenet144: 12-17.
Vajdic CM, Kricker A, Giblin M, McKenzie J, Aitken J, Giles GG & Armstrong BK (2002) Sun exposure predicts risk of ocular melanoma in Australia. Int J Cancer101: 175-182.
van den Bosch T, van Beek JG, Vaarwater J, Verdijk RM, Naus NC, Paridaens D, de Klein A & Kilic E (2012) Higher percentage of FISH-determined monosomy 3 and 8q amplification in uveal melanoma cells relate to poor patient prognosis. Invest Ophthalmol Vis Sci53: 2668-2674.
van Gils W, Lodder EM, Mensink HW, Kilic E, Naus NC, Bruggenwirth HT, van Ijcken W, Paridaens D, Luyten GP & de Klein A (2008) Gene expression profiling in uveal melanoma: two regions on 3p related to prognosis. Invest Ophthalmol Vis Sci49: 4254-4262.
van Hees CL, de Boer A, Jager MJ, Bleeker JC, Kakebeeke HM, Crijns MB, Vandenbroucke JP & Bergman W (1994) Are atypical nevi a risk factor for uveal melanoma? A case-control study. J Invest Dermatol103: 202-205.
Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM, Simpson EM, Barsh GS & Bastian BC (2009) Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature457: 599-602.
Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, Green G, Bouvier N, Sozen MM, Baimukanova G, Roy R, Heguy A, Dolgalev I, Khanin R, Busam K, Speicher MR, O'Brien J & Bastian BC (2010) Mutations in GNA11 in uveal melanoma. N Engl J Med363: 2191-2199.
Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG & Wilkinson KD (2008) BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res68: 6953-6962.
Verbeek AM (1985) Differential diagnosis of intraocular neoplasms with ultrasonography. Ultrasound Med Biol11: 163-170.
Virgili G, Gatta G, Ciccolallo L, Capocaccia R, Biggeri A, Crocetti E, Lutz J-M & Paci E. (2007). Incidence of Uveal Melanoma in Europe. In Ophthalmology, Vol. 114. pp. 2309-2315.e2302.
Vrabec TR, Augsburger JJ, Gamel JW, Brady LW, Hernandez C & Woodleigh R (1991) Impact of local tumor relapse on patient survival after cobalt 60 plaque radiotherapy. Ophthalmology98: 984-988.
Weber A, Hengge UR, Urbanik D, Markwart A, Mirmohammadsaegh A, Reichel MB, Wittekind C, Wiedemann P & Tannapfel A (2003) Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. Lab Invest83: 1771-1776.
Wei W, Mo J, Jie Y & Li B (2010) Adenoma of the retinal pigment epithelium: a report of 3 cases. Can J Ophthalmol45: 166-170.
White JS, McLean IW, Becker RL, Director-Myska AE & Nath J (2006) Correlation of comparative genomic hybridization results of 100 archival uveal melanomas with patient survival. Cancer Genet Cytogenet170: 29-39.
White VA, Chambers JD, Courtright PD, Chang WY & Horsman DE (1998) Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma. Cancer83: 354-359.
Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, Windpassinger C, Wackernagel W, Loy S, Wolf I, Viale A, Lash AE, Pirun M, Socci ND, Rutten A, Palmedo G, Abramson D, Offit K, Ott A, Becker JC, Cerroni L, Kutzner H, Bastian BC & Speicher MR (2011) Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet43: 1018-1021.
Wilder HC (1946) Intra-ocular tumors in soldiers, World War II. Mil Surg99: 459-490.
Wilson MW & Hungerford JL (1999) Comparison of episcleral plaque and proton beam radiation therapy for the treatment of choroidal melanoma. Ophthalmology106: 1579-1587.
Worley LA, Onken MD, Person E, Robirds D, Branson J, Char DH, Perry A & Harbour JW (2007) Transcriptomic versus chromosomal prognostic markers and clinical outcome in uveal melanoma. Clin Cancer Res13: 1466-1471.
Wu X, Zhu M, Fletcher JA, Giobbie-Hurder A & Hodi FS (2012) The protein kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanoma. PLoS One7: e29622.
Yang SS, Fu AD, McDonald HR, Johnson RN, Ai E & Jumper JM (2003) Massive spontaneous choroidal hemorrhage. Retina23: 139-144.
Zehetmayer M (2012) Stereotactic photon beam irradiation of uveal melanoma. Dev Ophthalmol49: 58-65.
Zehetmayer M, Kitz K, Menapace R, Ertl A, Heinzl H, Ruhswurm I, Georgopoulos M, Dieckmann K & Potter R (2000) Local tumor control and morbidity after one to three fractions of stereotactic external beam irradiation for uveal melanoma. Radiother Oncol55: 135-144.
Zhang J, Glatfelter AA, Taetle R & Trent JM (1999) Frequent alterations of evolutionarily conserved regions of chromosome 1 in human malignant melanoma. Cancer Genet Cytogenet111: 119-123.
Zografos L, Bercher L, Egger E, Chamot L, Gailloud C, Uffer S, Perret C & Markovits C (1992) [Treatment of eye tumors by accelerated proton beams. 7 years experience]
Le traitement des tumeurs oculaires par faisceau de protons acceleres. 7 ans d'experience. Klin Monbl Augenheilkd200: 431-435.
Zuidervaart W, van Nieuwpoort F, Stark M, Dijkman R, Packer L, Borgstein AM, Pavey S, van der Velden P, Out C, Jager MJ, Hayward NK & Gruis NA (2005) Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS. Br J Cancer92: 2032-2038.