enucleation was the standard treatment . in the early 1970s , radiotherapy and other treatment approaches , with the goal of preserving the eye , became increasingly popular .
external beam irradiation using charged particles , such as protons may conserve a useful level of vision , depending on the size of the tumor and its location with respect to the optic disc and macula .
protons deposit most of their energy near the end of their range , resulting in a uniform and highly localized dose being deposited largely in the tumor , sparing adjacent healthy tissue . furthermore ,
the liver is the most common site of metastatic disease ( einhorn et al 1974 ; char 1978 ; zakka et al 1980 ; rajpal et al 1983 ; diener - west et al 2001 ; kath et al 1993 ; bedikian et al 1995 ; coms 2001 , 2004 , 2005 ) .
diagnosis of metastasis is often followed by rapid physical decline of the patient and treatment is generally ineffective ( albert et al 1992 ) .
after diagnosis of choroidal melanoma , patients are screened for metastasis 6-monthly or annually , using liver function tests ( lfts ) and imaging studies .
more recently routine screening by ultrasonography of the liver and a panel of lfts have been recommended ( donoso et al 1985 ; donoso et al 1985 ; pach and robertson 1986 ; coms 1995 ; hicks 1998 ; eskelin et al 1999 ) .
our primary aim was to study the time interval between a diagnosis of melanoma and a diagnosis of metastasis , and the rates and sites of metastasis during follow - up time in our patients .
a secondary aim was to record ocular complications after proton beam irradiation ( seddon et al 1986 ) .
one hundred and fifty - two eyes of 152 patients with primary choroidal melanoma , whose primary treatment was either proton beam irradiation or enucleation , were included in the study .
subjects with clinical evidence of metastatic disease at the time of treatment or prior to the treatment of their intraocular tumor were excluded .
slit - lamp examination , biomicroscopy , indirect ophthalmoscopy , fundus photographs and a - scan and b - scan ultrasonography .
tumor height was measured and used to classify a tumor as small ( 1 mm to 2.5 mm in apical height ) , medium ( > 2.5 mm to 10 mm ) or large ( > 10 mm in apical height ) . tumor location and associated features , such as secondary retinal detachment and hemorrhage were recorded .
the initial evaluation also included fluorescein and indocyanine green angiography , computed tomography ( ct ) , and/or magnetic resonance imaging ( mri ) .
complete blood count , liver function tests ( aspartate aminotranspherase [ ast ] , alanine aminotranspherase [ alt ] , alkaline phosphatase [ aph ] , gamma - glutamyl transpeptidase [ -gt ] , lactate dehydrogenase [ ldh ] , carcinoembryonic antigen [ cea ] ) . ultrasound and ct or mri evaluation of the abdominal organs ( especially the liver ) and chest radiograph .
the patients from the proton beam irradiation group were admitted approximately two weeks before the scheduled date of irradiation . in the surgical suite ,
the tumor was localized using transillumination and indirect ophthalmoscopy , and four tantalum rings measuring 2.5 millimeters in diameter were sutured to the sclera to serve as references marking the tumor edges .
tumors located too far anteriorly were diagrammed using precise measurements , without the tantalum rings . during the irradiation sessions ,
the patient was seated and the head was immobilized using a custom - molded plastic mask .
lid retractors were used to remove the lid from the radiation field , and the patient was asked to fix his or her gaze on a light attached to the proton collimator .
the eye was viewed on a closed circuit television camera using high magnification , to detect any deviation from the indicated direction of gaze .
an imaging system was used to verify the eye s precise position during the treatment .
provided with the necessary data , the computer generated a three - dimensional model of the eye and tumor , which could be viewed from any desired angle . at the time the model also calculated the best direction of gaze , ideal shape of the field defining apertures , proton range and range modulations , the structures lying in the path of the beam , and what the viewer should see in the alignment film used when aiming the beam .
the rectus muscles were individually hooked and cut with scissors near their insertion into the sclera .
the enucleation scissors were placed between tenon s capsule and the sclera , the optic nerve was cut and the eye removed . an orbital implant ( hydroxyapatite sphere )
following enucleation , eyes were processed for histopathologic confirmation of the diagnosis at the pathology laboratory of athens general hospital .
the patients were re - examined 6-monthly for the first 5 years and annually thereafter .
follow - up evaluation included : slit - lamp examination , biomicroscopy , indirect ophthalmoscopy , fundus photographs and a - scan and b - scan ultrasonography .
complete blood count , liver function tests ( ast , alt , aph , -gt , ldh , cea ) . ultrasound evaluation of the abdominal organs ( especially the liver ) . in case of abnormal findings , ct or mri scan of the liver and/or biopsy or cytologic tests
slit - lamp examination , biomicroscopy , indirect ophthalmoscopy , fundus photographs and a - scan and b - scan ultrasonography .
tumor height was measured and used to classify a tumor as small ( 1 mm to 2.5 mm in apical height ) , medium ( > 2.5 mm to 10 mm ) or large ( > 10 mm in apical height ) . tumor location and associated features , such as secondary retinal detachment and hemorrhage were recorded .
the initial evaluation also included fluorescein and indocyanine green angiography , computed tomography ( ct ) , and/or magnetic resonance imaging ( mri ) .
complete blood count , liver function tests ( aspartate aminotranspherase [ ast ] , alanine aminotranspherase [ alt ] , alkaline phosphatase [ aph ] , gamma - glutamyl transpeptidase [ -gt ] , lactate dehydrogenase [ ldh ] , carcinoembryonic antigen [ cea ] ) . ultrasound and ct or mri evaluation of the abdominal organs ( especially the liver ) and chest radiograph .
the patients from the proton beam irradiation group were admitted approximately two weeks before the scheduled date of irradiation . in the surgical suite , the tumor was localized using transillumination and indirect ophthalmoscopy , and four tantalum rings measuring 2.5 millimeters in diameter were sutured to the sclera to serve as references marking the tumor edges .
tumors located too far anteriorly were diagrammed using precise measurements , without the tantalum rings . during the irradiation sessions
, the patient was seated and the head was immobilized using a custom - molded plastic mask .
lid retractors were used to remove the lid from the radiation field , and the patient was asked to fix his or her gaze on a light attached to the proton collimator .
the eye was viewed on a closed circuit television camera using high magnification , to detect any deviation from the indicated direction of gaze .
an imaging system was used to verify the eye s precise position during the treatment .
provided with the necessary data , the computer generated a three - dimensional model of the eye and tumor , which could be viewed from any desired angle . at the time the model also calculated the best direction of gaze , ideal shape of the field defining apertures , proton range and range modulations , the structures lying in the path of the beam , and what the viewer should see in the alignment film used when aiming the beam .
enucleation was performed at the department of ophthalmology of the university of athens . the surgical technique consisted of peritomy for 360 at the limbus .
the rectus muscles were individually hooked and cut with scissors near their insertion into the sclera .
the enucleation scissors were placed between tenon s capsule and the sclera , the optic nerve was cut and the eye removed . an orbital implant ( hydroxyapatite sphere ) was placed in the socket and the muscles were sutured to the implant .
following enucleation , eyes were processed for histopathologic confirmation of the diagnosis at the pathology laboratory of athens general hospital .
the patients were re - examined 6-monthly for the first 5 years and annually thereafter .
follow - up evaluation included : slit - lamp examination , biomicroscopy , indirect ophthalmoscopy , fundus photographs and a - scan and b - scan ultrasonography .
complete blood count , liver function tests ( ast , alt , aph , -gt , ldh , cea ) . ultrasound evaluation of the abdominal organs ( especially the liver ) . in case of abnormal findings , ct or mri scan of the liver and/or biopsy or cytologic tests were required to confirm or rule out metastatic disease .
slit - lamp examination , biomicroscopy , indirect ophthalmoscopy , fundus photographs and a - scan and b - scan ultrasonography .
tumor height was measured and used to classify a tumor as small ( 1 mm to 2.5 mm in apical height ) , medium ( > 2.5 mm to 10 mm ) or large ( > 10 mm in apical height ) . tumor location and associated features , such as secondary retinal detachment and hemorrhage were recorded .
the initial evaluation also included fluorescein and indocyanine green angiography , computed tomography ( ct ) , and/or magnetic resonance imaging ( mri ) .
complete blood count , liver function tests ( aspartate aminotranspherase [ ast ] , alanine aminotranspherase [ alt ] , alkaline phosphatase [ aph ] , gamma - glutamyl transpeptidase [ -gt ] , lactate dehydrogenase [ ldh ] , carcinoembryonic antigen [ cea ] ) . ultrasound and ct or mri evaluation of the abdominal organs ( especially the liver ) and chest radiograph .
the patients from the proton beam irradiation group were admitted approximately two weeks before the scheduled date of irradiation . in the surgical suite , the tumor was localized using transillumination and indirect ophthalmoscopy , and four tantalum rings measuring 2.5 millimeters in diameter were sutured to the sclera to serve as references marking the tumor edges .
tumors located too far anteriorly were diagrammed using precise measurements , without the tantalum rings . during the irradiation sessions ,
the patient was seated and the head was immobilized using a custom - molded plastic mask .
lid retractors were used to remove the lid from the radiation field , and the patient was asked to fix his or her gaze on a light attached to the proton collimator .
the eye was viewed on a closed circuit television camera using high magnification , to detect any deviation from the indicated direction of gaze .
an imaging system was used to verify the eye s precise position during the treatment .
a computer planning program was used to target the proton beam . provided with the necessary data , the computer generated a three - dimensional model of the eye and tumor , which could be viewed from any desired angle . at the time the model also calculated the best direction of gaze , ideal shape of the field defining apertures , proton range and range modulations , the structures lying in the path of the beam , and what the viewer should see in the alignment film used when aiming the beam .
enucleation was performed at the department of ophthalmology of the university of athens . the surgical technique consisted of peritomy for 360 at the limbus .
the rectus muscles were individually hooked and cut with scissors near their insertion into the sclera .
the enucleation scissors were placed between tenon s capsule and the sclera , the optic nerve was cut and the eye removed . an orbital implant ( hydroxyapatite sphere )
following enucleation , eyes were processed for histopathologic confirmation of the diagnosis at the pathology laboratory of athens general hospital .
the patients were re - examined 6-monthly for the first 5 years and annually thereafter .
slit - lamp examination , biomicroscopy , indirect ophthalmoscopy , fundus photographs and a - scan and b - scan ultrasonography .
complete blood count , liver function tests ( ast , alt , aph , -gt , ldh , cea ) . ultrasound evaluation of the abdominal organs ( especially the liver ) . in case of abnormal findings , ct or mri scan of the liver and/or biopsy or cytologic tests were required to confirm or rule out metastatic disease .
tumor thickness according to b - scan ultrasonography , tumor location according to binocular indirect ophthalmoscopy , and goldmann triple mirror examination were recorded . in the enucleation group
the affected eye was the right one in 18 ( 58% ) patients and the left one in 13 ( 42% ) .
tumor thickness ranged from 4.6 mm to 13.4 mm with a mean value of 9.7 mm .
tumor location was superior in 6 ( 19.4% ) patients , inferior in 4 ( 12.9% ) patients , temporal in 7 ( 22.6% ) patients , nasal in 4 ( 12.9% ) patients , superior / temporal in 2 ( 6.4% ) patients , inferior / temporal in 4 ( 12.9% ) patients , and inferior / nasal in 4 ( 12.9% ) patients ( figure 1 ) . in the irradiation group ,
the affected eye was the right one in 57 ( 47% ) patients and the left one in 64 ( 53% ) .
tumor thickness ranged from 2.6 mm to 13.4 mm with a mean value of 7.3 mm .
tumor location was superior in 22 ( 18.2% ) patients , inferior in 18 ( 14.9% ) patients , temporal in 20 ( 16.5% ) patients , nasal in 8 ( 6.6% ) patients , superior / temporal in 13 ( 10.7% ) patients , superior / nasal in 4 ( 3.3% ) patients , inferior / temporal in 26 ( 21.5% ) patients and inferior / nasal in 10 ( 8.3% ) patients ( figure 1 ) .
of the152 patients in our study , 31 were treated by enucleation between 1992 and 2006 ( 16 males , 15 females ) .
of the 31 patients , 6 ( 19.3% ) were diagnosed with metastasis ( 5 males , 1 female ) .
the metastatic sites included : liver ( 5 patients , 16.1% of enucleation group , 83.3% of the patients with metastasis ) and skin ( 1 patient , 3.2% of enucleation group , 16.7% of the patients with metastasis ) ( figure 2 ) .
the median interval time from diagnosis of choroidal melanoma to diagnosis of metastasis was 29.5 months ( 2.46 years ) . at 5 years , 5 patients were diagnosed with metastasis ( 16.1% of enucleation group , 83.3% of patients with metastasis ) . between 1992 and 2006 , 121 patients were treated by proton beam irradiation ( 53 males , 68 females ) .
thirteen patients ( 10.7% ) were diagnosed with metastasis ( 7 males , 6 females ) .
the metastatic sites included : liver ( 8 patients , 6.6% of irradiation group , 61.5% of the patients with metastasis ) , lung ( 2 patients , 1.6% of irradiation group , 15.4% of the patients with metastasis ) , brain ( 1 patient , 0.8% of irradiation group , 7.7% of the patients with metastasis ) , thyroid ( 1 patient , 0.8% of irradiation group , 7.7% of the patients with metastasis ) , and colon ( 1 patient , 0.8% of irradiation group , 7.7% of the patients with metastasis ) ( figure 2 ) .
the median interval of time from diagnosis of choroidal melanoma to the diagnosis of metastasis was 44.8 months ( 3.7 years ) . at 5 years
, 10 patients were diagnosed with metastasis ( 8.3% of irradiation group , 76.9% of patients with metastasis ) .
ocular complications were recorded after proton beam irradiation , according to slit - lamp examination , biomicroscopy , indirect ophthalmoscopy , fundus photographs , and a - scan and b - scan ultrasonography .
anterior segment complications were recorded in 99 ( 81.8% ) patients and posterior segment complications in 71 ( 58.7% ) patients .
cataract was recorded in 59 ( 48.7% ) patients , iris neovascularization in 17 ( 14% ) patients , neovascular glaucoma in 14 ( 11.6% ) patients , and corneal opacification in 9 ( 7.4% ) patients .
secondary retinal detachment was recorded in 25 ( 20.7% ) patients , retinopathy in 17 ( 14% ) patients , vitreous hemorrhage in 17 ( 14% ) patients and optic neuropathy in 12 ( 9.9% ) patients ( figure 3 ) .
for more than a century , enucleation has been the standard treatment for choroidal melanoma .
however , concerns about enucleation , especially possible tumor spread caused by manipulation of the eye during surgery , plus vision loss and the poor cosmetic outcome , have made irradiation therapy a popular alternative .
when patients are deciding on their treatment for choroidal melanoma , the major influences on their decision are fear of death due to cancer , and concerns about the prognosis of vision in the affected eye .
many ophthalmologists assume that better results can be achieved with irradiation therapy , because this form of treatment potentially allows the retention of some vision and avoids the perception of disfigurement .
a 1986 study ( gragoudas et al 1987 ) showed a 20% cumulative risk of developing metastasis 5 years after irradiation , based on 128 patients followed for a median of 5.4 years . in a study ( gragoudas et al 1988 ) of 780 eyes ( which included many of the 128 noted above ) followed for a median of 2.2 years , 8% of that study population actually developed metastases , the median time to detection being 2.1 years .
based on kaplan - meier probability curves , the same 5-year estimate of a 20% cumulative risk of metastasis was determined .
eighty percent to 90% of metastases from uveal melanoma occurred in the liver in those patients , less common sites being the skin and lung . in our study
we recorded the tumor location , the rates and sites of metastasis , and the time from diagnosis of melanoma to diagnosis of metastasis . in the enucleation group ,
the median time from diagnosis of choroidal melanoma to diagnosis of metastasis was 29.5 months ( 2.46 years ) .
five of the 6 patients with metastasis ( 83.3% ) were diagnosed within the first 5 years after treatment ( enucleation ) . in the irradiation group ,
the median time from diagnosis of choroidal melanoma to diagnosis of metastasis was 44.8 months ( 3.7 years ) .
ten of the 13 patients with metastasis ( 76.9% ) were diagnosed within the first 5 years after treatment ( irradiation ) .
important prognostic factors for death from metastatic melanoma include the size of the tumor ( the larger the tumor , the worse the prognosis ) , the location of the tumor ( tumors within the ciliary body are associated with a poorer prognosis than those confined to the choroid ) , the age of the patient at the time of diagnosis ( the older the patient , the worse the short - term survival prognosis ) and extrascleral tumor extension ( augsburger and gamel 1990 ) .
patients with choroidal melanoma are advised to undergo periodic examination , blood tests for liver enzyme levels and imaging studies , such as chest radiographs and ultrasonography or mri of the liver .
we agree with other studies ( hicks 1998 ; eskelin et al 1999 ) that periodic screening for metastatic uveal melanoma is primarily beneficial , when effective treatment is available or when patients are eligible as candidates for clinical trials of promising treatment .
such therapies are needed given the potentially frequent occurrence of micro - metastasis at the time of diagnosis of choroidal melanoma and the high incidence of metastasis detected clinically after diagnosis of the primary tumor .
many treated eyes eventually lose a substantial amount of vision , as a consequence of complications after radiation therapy .
factors that influence how much vision will be lost include the location of the posterior edge of the tumor relative to the optic disc and fovea , the visual acuity before treatment , the presence or absence of macular retinal detachment , and the thickness of the tumor .
some systemic factors , such as diabetes mellitus , may also worsen a patient s prognosis for retention of useful vision ( seddon et al 1986 ) .
retinal detachment , optic neuropathy , radiation retinopathy , neovascular glaucoma ( kim et al 1986 ; summanen et al 1996 ; daftari et al 1997 ) , vitreous hemorrhage , and cataract ( meecham et al 1994 ; gragoudas et al 1995 ) have emerged consistently as causes of visual loss in proton beam - irradiated eyes . establishing which of these conditions is most influential in any given case may cause difficulty , as they may occur in the same patient , in whom the presence of a cataract may further hamper a view of the fundus . in our study , irradiation - related complications involving the anterior segment , which contributed to a decline in visual acuity or eye loss , included cataract ( 59 patients ; 48.7% ) , neovascular glaucoma ( 14 patients ; 11.6% ) , and corneal neovascularization and opacification ( 9 patients ; 7.4% ) .
gragoudas and colleagues ( 1995 ) showed that 42% of 383 patients who received proton beam irradiation for uveal melanoma , developed new posterior subcapsular opacities in direct proportion to the dose of radiation received by the lens in the irradiated eye .
this result was determined by a computer - generated dose - volume assessment routinely calculated at the time of irradiation .
cortical and sclerotic opacities were found to be correlated only with age in this study .
cataract extraction is feasible in these patients and can restore vision in some ( augsburger and shields 1985 ; fish et al 1991 ; gragoudas et al 1992 ) .
panretinal photocoagulation can substantially reduce the severity of neovascular glaucoma and reduce the risk of enucleation by half ( kim et al 1986 ) . in our study ,
posterior segment complications included secondary retinal detachment ( 25 patients ; 20.7% ) , radiation retinopathy ( 17 patients ; 14% ) , vitreous hemorrhage ( 17 patients ; 14% ) , and radiation neuropathy ( 12 patients ; 9.9% ) .
maculopathy affects central vision ( gragoudas et al 1992 ; gunduz et al 1999 ; guyer et al 1992 ) , whereas papillopathy can lead to total loss of vision ( guyer et al 1992 ; gragoudas et al 1999 ) .
patients who develop a blind , painful eye must undergo enucleation ( kellner et al 1993 ) .
preservation of the eye and useful vision in many patients are the obvious advantages of conservative treatment with radiation compared with enucleation .
however questions have been raised regarding the efficacy of this treatment in limiting metastatic spread of the tumor .
observational studies ( egan et al 1989 ; seddon et al 1990 ; augsburger et al 1986 ) comparing irradiation with enucleation have indicated no significant differences in survival rates . in the collaborative ocular melanoma study (
adams et al 1998 ) , overall 5-year mortality rates were comparable in patients treated by enucleation and by plaque radio - therapy ( iodine 125 ) .
many patients maintain some degree of function in the eye for long periods after treatment .
overall rates of metastatic disease are comparable to those observed after enucleation ; thus , enucleation should be limited to patients with large tumors in whom the eye is unlikely to be salvaged by irradiation .
doubtless continued refinement of current methods , and development of new techniques , will further improve the outlook of patients with uveal melanomas .
in our series , 10.7% of the irradiation group and 19.3% of the enucleation group were diagnosed with metastasis .
this difference is attributed to the larger tumor dimensions in patients of the enucleation group , given the observed correlation between increased metastasis rate and increased size of choroidal melanoma .
effective methods are needed to prevent , diagnose , and treat metastasis from choroidal melanoma .
 purposeto investigate tumor thickness and location , the interval of time between treatment for choroidal melanoma ( proton beam irradiation or enucleation ) and diagnosis of metastatic disease , and rates and sites of metastasis.designretrospective , interventional , noncomparative case series.methodsfollow-up of 152 patients with primary choroidal melanoma , between 1992 and 2006 ( 14 years ) . 
 one hundred and twenty - one patients were treated with proton beam irradiation and 31 patients were treated with enucleation . 
 baseline and annual or semiannual ophthalmic examination , b - scan ultrasonography , systemic and laboratory evaluations ( liver enzymes , chest x - ray , ultrasonography or magnetic resonance imaging of the liver ) were performed according to a standard protocol.resultsnineteen patients ( 12.5% ) were diagnosed with metastasis during follow - up time after treatment for choroidal melanoma . 
 thirteen patients ( 10.7% ) of the irradiation group and 6 patients ( 19.3% ) of the enucleation group were diagnosed with metastasis . 
 eight patients ( 6.6% ) of the irradiation group and 5 patients ( 16.1% ) of the enucleation group were diagnosed with liver metastasis . 
 ocular complications after proton beam irradiation were recorded . 
 fifty - nine patients ( 48.7% ) of the irradiation group presented with cataract . 
 other complications were retinal detachment , retinopathy , vitreous haemorrhage , iris neovascularization , neovascular glaucoma , optic neuropathy , and corneal opacification.conclusionsin our series , 10.7% of the irradiation group and 19.3% of the enucleation group were diagnosed with metastasis . the liver was the most common site of metastasis in both groups . 
 cataract was the most common complication in the irradiation group . 
Introduction
Methods
Initial evaluation included
Ophthalmic examination
Systemic evaluation
Ophthalmic examination
Systemic evaluation
Results
Discussion
Conclusion