Grand rounds Clay Bundrick, MD LSU Dept of Ophthalmology

Presentation  CC: “eye doctor told me I had retinal detachment”  HPI: 55yo WM no sig PMH presented to LSU eye clinic 2/2012 with 2 year history of progressively deteriorating vision left eye.  + metamorphopsia, photopsia, “ball of light would travel across VF 3x/day  almost sudden acute drop in VA brought him to optometrist in Alexandria who referred him to LSU  SH: skidder operator, smokes 1.5ppd, 4+ EtOH  POH: none  FH/FOH: noncontributory

exam  Vitals: BP 144/86, HR 78, RR 16, T 98f  VAsc: 20/20 OD, 20/400 OS  Pupils: APD left eye  CF: constricted OS  EOMs: full  Ta: 17 OU

exam  SLE  LLL: no proptosis, no masses, +anterior blepharitis  C/S: trace injection OU  K: clear ou  AC: deep/ quiet OU  Lens: N1 nsc ou

DFE

Differential Dx:  Choroidal nevus  Choroidal melanoma  Focal choroidal hemangioma  Melanocytoma  Metastasis  ARMD  CHRPE  Suprachoroidal detachment

Choroidal melanoma?  Next steps in diagnosis?  Gonioscopy to check for anterior tumors  FA  US  CT/ MRI/ bloodwork  Biopsy  ** Gold standard: indirect ophthalmoscopy usually sufficient for diagnosis

FA  Usually limited dx value bc no pathognomonic pattern  Late hyperfluorescence classically found  Collar stud tumors show “dual circulation” of tumor vessels and retinal vessels Collar stud – when tumor breaks through bruch’s membrane

US  US useful with opaque media and to measure the lesion  Also ID’s extraocular extension  Classic findings:  Acoustic hollowness  Choroidal excavation  Orbital shadowing  Top: US of dome shaped tumor that demonstrates choroidal excavation  Bottom: collar stud tumor

IMAGING  MRI shows hyperintensity in T1- weighted images and hypointensity in T2  Gadolinium enhances optic nerve and orbital invasion  This is a T1 saggital view

Labs/ other imaging  CBC/ BMP WNL  AST slightly elevated relative to ALT  No obvious mets in liver/ lungs

Choroidal Melanoma  Incidence 5/1,000,000 per year  No gender preference  Main peak age 55-65, smaller peak age  Can occur in children but rare (better px)  Most common primary intraocular malignancy in adults  **cutaneous melanoma 20x more common than intraocular  Accounts for 90% of uveal melanomas

Choroidal melanoma  Risk factors  Ocular melanocytic conditions (oculodermal melanocytosis)  Cigarette smoking  Northern European background  Light irides (inferior ½)  Sun? probably, but no definitive data

Classification by cell type  Spindle cell  Arranged in tight bundles  Cell membranes indistinct  Granular cytoplasm

Classification by cell type  Epithelioid cells  Larger  More pleomorphic  Polyhedral  Abundant cytoplasm  Distinct cell membranes  Large nuclei/nucleoli  More abundant mitotic figures

 Collar stud tumor  Penetration of bruch’s

Callender classification system  Best to worst prognosis:  Spindle cell nevus : only spindle A cells  Spindle cell melanoma : spindle A+B cells  Mixed melanoma : spindle + epithelioid  Epithelioid melanoma : exclusively ep cells

Categorize by size Diameter (mm) Thickness (mm) 5 year survival % Small Medium Large>16>1050

Poor prognosticators  Histology: epithelioid  Chromosomal abnormalities within melanoma cells:  Loss in chm 3 and gains in chm 8 bad  Gains in chm 6 short arm good  Size: big is bad  Extrascleral extension, scleral contact  Location: anterior tumors (ciliary body) worse, more likely to have spread.

Metastasize?  It is not known at what stage melanomas begin to spread  2% of ocular melanoma have demonstrable mets at time of diagnosis  COMS found that 10% of patients harbored a second malignancy  If suspicion of metastatic disease is high bc of large tumor size / systemic symptoms- common to get PET scan, more sensitive

Metastasize?  Pattern of spread:  Hematogenous  Via bruch’s penetration  invasion of scleral channels for blood vessels  vortex veins  Primarily to the liver, occasionally lungs, bone, skin, brain  Rarely invades optic nerve  7 years  median duration from Rx to Dx of mets  6 months  from dx of mets to death

Fundus exam  Elevated  Subretinal dome-shaped mass  From highly pigmented to amelanotic

Fundus exam  Lipofuscin/ orange pigment clumps commonly seen in RPE overlying tumor  Collar stud with visible intrinsic blood vessels

Fundus exam  Diffuse tumor  Rare  Characterized by extensive flat grayish brown irregular discoloration  Extraocular extension common bc this type tends to be aggressive

Fundus exam  Subtotal retinal detachment  Unlike RRD:  Subretinal fluid shifts with ocular movement and gravity  Retina does not show the fine silvery rippling that occurs in the presence of a tear

treatment  Goals:  1. conserve as much useful vision as possible  2. avoid development of painful and unsightly eye  Observation alone is acceptable if:  1. tumor is <1mm thick  2. pt cannot tolerate tretment  Risks involved in delaying Rx are uncertain, so it is essential to confirm dx and obtain proper consent from an understanding pt

treatment  Enucleation  - treatment of choice for all large tumors and many medium size tumors  If there is optic nerve invasion  Extensive involvement of ciliary body or angle  Irreversible loss of useful vision  Poor motivation to keep the eye  Crucial to operate on the correct eye  Orbital recurrence is rare if there is no extraoc tumor spread

Radiation Therapy  BRACHYTHERAPY  With ruthenium-106 or iodine 125  Indications  Tumors <20mm in basal d  +chance of salvaging vision  Can treat tumors up to 5mm thick with ruthenium plaque and 10mm thick with iodine plaque  COMS- pre enucleation XRBT:  no effect on overall survival  Did significantly reduce orbital recurence

 TECHNIQUE  Tumor localized by transillumination  Template with transparent metal ring with eyelets sutured to sclera  Sutures are loosened and used to secure the radioctive plaque  Plaque is removed 3-7 days after the appropriate dose has been delivered  Usually >80Gy  Tumor regression starts abt 1-2 mo after rx

 Brachytherapy  Tumor response usually gradual  Amelanotic tumors tend to become more pigmented  Complications  Cataract  Papillopathy  Macular edema (refractory to grid laser)  NVG  Toxic tumor syndrome  Complications worse in diabetics

Radiation therapy  Plaque radiotherapy  Radiation focused on tumor by aiming beams from different directions sequentially or concurrently  Good tumor control rate  Adverse effects include  Radiation retinopathy  Optic neuropathy

Radiation therapy  CHARGED PARTICLE IRRADIATION  Irradiate with protons achieves high dose in tumor and small doses in superficial tissues  Indications  Tumors unsuitable for brachytherapy bc too large or posterior (unreliable plaque placement)  Tumor regression slower than brachyrx  Complications more anterior (cataracts/ NVG)

Chemo?  Concern for undetected mets common  adjuvant systemic treatment is not advocated.  This consensus comes from treatment trials with extrapolation of the experience with cutaneous melanoma, where adjuvant treatment has shown no benefit.  In cases where distant metastases are found during the initial systemic workup, treatment of the intraocular melanomas becomes palliative..

COMS  Collaborative Ocular Melamoma Study  Three subgroups based on tumor size:  1. Small tumors  Treatment vs observation  Results: ?? Enrollment in Rx branch too low for comparison  2. Medium tumors  Enucleation vs plaque RT  Rx modality did not affect 5 year survival  3. large tumors  Enuclation with preop RT vs no preop RT  Preop RT did not affect 5 year survival

prognosis  Guarded  About 30-50% of patients with choroidal melanoma will die within 10 years from diagnosis and treatment.  Death is usually secondary to distant metastases, and the risk is greatest in larger tumors.  For large melanomas, the Collaborative Ocular Melanoma Study found that the 10-year rates of death secondary to metastasis were 45% in the pre- enucleation radiation group and 40% in the enucleation alone group.

DDX  Choroidal nevus  5-10% of whites, rare in blacks  Assd with NF1 and dysplastic nevus syndrome  Growth usually prior to puberty, rare in adulthood  For this reason a growing lesion in an adult should be worrisome  Usually asymptomatic, detected on routine exam

Choroidal nevus  Usually <5mm basal diameter and 1mm thick  Slate blue or grey, not sharp borders  Histologically demonstrate spindle cell melanocytes in the choroid but spare the choriocapillaris

Choroidal nevus  Surface drusen may be present, particularly in central area  FA findings depend on amount of pigmentation  Most nevi are avascular and pigmented  Hypofluor caused by blockage of background choroidal fluorescence  Surface drusen will result in dots of hyperf  FA is not helpful in dist bt small melanoma and a nevus, althought pinpoint areas of hyperf may predict future growth

Choroidal nevus  ICG shows hypofluorescence  US shows localized flat/ slightly elevated lesion with hight internal acoustic reflectivity  Low internal reflectivity on a-scan suggests malignancy

 Fishy features  Symptoms of blurred vision etc  Dimensions > 5mm/ 1mm  Orange pigment  Margin near optic nerve  Serous RD over surface of lesion Suspicious nevus Amelanotic nevus Halo nevus

Ddx… melanocytoma  Magnocellular nevus  Rare, distinctive heavily pigmented tumor  MC in optic nerve head  Rarely arises elsewhere in uvea  More common in dark skinned females  Usually stationary with little tendency to change

melanocytoma  Histology  Large deeply pigmented polyhedral spindle cells  Small nuclei

melanocytoma  Dark lesion with feathery edges  Within NFL  Extends over edge of disk  Occasionally tumor is elevated and occupies most of the disk surface  APD may be present with good vision

melanocytoma  FA  Hypofluorescence of deep vessels due to blockage  RX:  Rarely required  Except in event of malignant transformation

DDx choroidal hemangioma  Not usually assd with systemic disease  May be dormant thoughout life or may give rise to s/o in adulthood secondary to exudative RD  Slight progressive enlargement may occur over many years  Presentation usually in 4 th / 5 th decades:  Unilateral blurring of VA/ VF defect  Hyperopia from subretinal fluid/ tumor  Most asymptomatic

Circumscribed choroidal hemangioma  Histology shows congested vascular channels  Oval mass with indistinct margins, same color as surrounding choroid  Usually posterior to equator in peripapillary area  Median base diameter is 6mm, median thickness 3mm

Circumscribed choroidal hemangioma  FA  Rapid, spotty hyperfluorescence in the prearterial phase and diffuse intense late hyperfluorescence  ICG  Early hyperfluorescence

Circumscribed choroidal hemangioma  US  Acoustically solid lesion with sharp anterior surface but without choroidal excavation and orbital shadowing  Complications:  Fibrous metaplasia  Retinal edema/ exudative RD/ NVG

Circumscribed choroidal hemangioma  Treatment  Unnecessary in asymptomatic lesions  PDT- same as for choroidal NVM  TTT- transpupillary thermotherapy for lesions not involving the macula- causes VF loss  RT- low dose, causes collateral damage

Diffuse Choroidal Hemangioma  Usually affects over half of the choroid  Enlarges very slowly  Almost exclusively in pts with SWS  Ipsilateral to the nevus flammeus

Diffuse choroidal hemangioma  Deep red tomato ketchup fundus  Most marked at posterior pole  US shows diffuse choroidal thickening  Complications:  Cystoid retinal degeneration  Exdative rd  Nvg  Rx: external beam radiotherapy  Rarely necessary

CHRPE  Common benign lesion of RPE  May be typical or atypical  Discrete margins  Depigmented lacunae common  Grouped bear tracks alert clinician for polyps

references  1. Factors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol. Dec 1997;115(12):  2. Accuracy of diagnosis of choroidal melanomas in the COMS Arch Ophthalmol. Sep 1990;108(9): [Medline]. Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jöckel KH, Becher R.Arch Ophthalmol. Sep 1990;108(9): [Medline]. Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jöckel KH, Becher R.  3. Prognostic implications of monosomy 3 in uveal melanoma. Lancet. May ;347(9010): [Medline]. 3. Prognostic implications of monosomy 3 in uveal melanoma. Lancet. May ;347(9010): [Medline].  4. Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no. 6. Am J Ophthalmol. Jun 1998;125(6): [Medline]. 4. Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no. 6. Am J Ophthalmol. Jun 1998;125(6): [Medline].  5. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre- enucleation radiation of large choroidal melanoma III: local complications and observations following enucleation COMS report no. 11. Am J Ophthalmol. Sep 1998;126(3): [Medline]. 5. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre- enucleation radiation of large choroidal melanoma III: local complications and observations following enucleation COMS report no. 11. Am J Ophthalmol. Sep 1998;126(3): [Medline].  6. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre- enucleation radiation of large choroidal melanoma II: initial mortality findings. COMS report no. 10. Am J Ophthalmol. Jun 1998;125(6): [Medline]. 6. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre- enucleation radiation of large choroidal melanoma II: initial mortality findings. COMS report no. 10. Am J Ophthalmol. Jun 1998;125(6):