Benign. ú Not cancerous Glioma ú Growth is only LOCAL BUT. Malignant. Ocular tumors: Can vary in so many ways

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1 TERMINOLOGY Tip of the iceberg Diana Shechtman OD FAAO Benign ú Not cancerous Glioma ú Growth is only LOCAL BUT Malignant ú RAPID out of control cell proliferation resulting in organ function damage. They can spread near by tissue or Metastasize (infiltration into other tissues/organs) Choroidal melanoma Ocular tumors: Can vary in so many ways Location ú ONH, retina & choroid Size/Shape ú Thickness ú Multi- lobulated ú Diffused or localized Vascular vs melanin vs others ú vascular ones are commonly associated leakage exudate, heme, fluid Laterality ú Some bilateral may be associated with syndrome Color (dark, white, red ) DARK/ well delineated borders Flat = CHRPE White mulberry = astrocytoma Large dark elevated = chroroidal melanoma Red & Diffuse = choroidal hemangioma GENERAL RULES Red enveloped circular with a feeding artery & draining vein = capillary hemangioma Von Hippel-Lindau (VHL) disease & RCH ` Wyburn-Mason Syndrome & AVM (Racemose) Creamy white mildly elevated= choroidal metastases Yellowish plaque (rough) like lesion = osteoma GENERAL RULES Cavernous hemangioma may be associated w CH of brain Carvenous = filled w vascular sinus 1

2 Appreciating a true GRAPE like cluster of a cavernous hemangioma Choroidal Nevi: BENIGN proliferation (neoplams) of choroidal melanocytes 6-10% (blue mnt eye study) prevalence among whites % do vary Greenstein et al. Prevalence of nevi. Ophthal. 12/ mill Americans have a nevi No correlation w (+)FHx of any melanoma < 3 mm elevation Typically FLAT < 3 DD in size ú 90% are <2 DD; so if note ú 3-5DD it is questionable Incomplete Shadowing Note drusen Shan Ophthalmology 2012 EDI features enhances choroidal view" OCT uses in lesions: Nevus or melanomas Accurate measurements HEIGHT even if <1mm to follow over time far more accessible than ultrasonography DIMENSION easily follow growth over time through objective measurements Note the choriocapillaries absence NON-EDI under view lesion of a flat nevus" (helps delineate borders) in this complete shadowing lesion Shields EDI OCT of small choroidal melanoma Arch Opth 2012 (n=37 small melanomas) Lateral dimensions" OCT choroidal" lesion" 3200um 1500um sclera" Controversy with the ultrasound" >2-3mm thickness = melanoma! Note: OCT thickness is 50% thinner than ultrasound" Increase thickness (100%) PIL is describe as shaggy Subretinal fluid May be noted in nevus but far more common in a melanoma RPE atrophy 41% Drusen ~40% Thickness, if any <2mm PIL is loss/attenuation Subretinal fluid only 16% Shields EDI OCT of small choroidal melanoma Arch Opth 2012 (n=37 small melanomas) 2

3 FA/ICG provides NO help in the evaluation of a nevus Basic nevus management FA FA: Only observe hyperfl correspond to RPE alternation/drusen In late phase ICG: due ot fact that it can penetrate the RPE shows hypofl of the lesion 90D/BIO Photos Consider OCT ú Documenet height/size ú check fluid & morphological changes May document height w ultrasound ú if suspicious (large or thicken) ICG To Find Small Ocular Melanoma Shields CL, et al "Choroidal nevus transformation into melanoma. Analysis of 2,514 consecutive cases" Arch Ophthalmol 2009; 127(8): Why is identifying a small melanoma critical? SIZE does mater 1. THE 5 yr mortality rate after enucleation: 16% small choroidal melanoma, 32% medium & 53% for large 2. 1mm increase thickness = 5% increase risk of metastatic dz ( 10 yrs) 3. Despite direct tx of the choroidal melanoma, 30-50% of pts develop metastatic disease COMS 1998 Symptoms VFD, metamorphopsia Photopsia & VL (dep on location) No signs: annual exam <3% chance of growth Fluid (subretinal) Thickness >2mm Increase risk of metastasis 1-2 signs: 4-6M f/u (sooner after initial Dx) 38% FAF chance of growth Margins near ON > 3 signs: consultation (W/I 3mm) 50% chance of growth over 5 yrs Management depends on # of features noted Orange pigment (lipofuscin) pathognomonic UHHD was addedc in 2009 using helpful hints daily Choroidal Melanoma: Melanoma cells undergo neoplasia w evidence of rapid growth ~6 (4-10.9) cases/million/yr Most common primary malignant intraocular tumor ú 85% of intra- ocular tumor (uveal) Not seen in young pts ú Peak incidence (older pt) Highly malignant & progressive May metastasize to other organs 3

4 Choroidal Melanoma: correlation White pts UV might increase the risk of uveal melanoma, but the role and direct correlation of exposure remains inconclusive ú Light eyes, fair skin, propensity to burn, has freckles increase risk Degree of pigmentation and cutaneous mole also appear to be markers of risk Melanomas are commonly located near posterior pole Choroidal melanoma Present as GREEN, dull gray, dark brown or even yellow elevated lesions SINGLE LESION ú Not typically MULTIPLE Amelonic is NOT as typical and should Choroidal Melanoma be suspected to be a Choroida metastases >3 mm elevation ú 30% may be <3mm Usually >5mm in size ú >7-8DD in size (1.5mm =1DD) Overlying pigment may also be variable but associated significant hemes is RARE Are you worried about this lesion? Melanoma location ú ~20% to be Superior, nasal, inferior or temporal ú 28% are temporal ú Only 4% of melanoma are near the macula The tests that help in the evaluation Ultrasonography OCT FA FAF Shields uveal melanoma analysis n=

5 Subretinal fluid is far more common in melanoma" Best evaluated through use of OCT" Height measurements ultrasound vs OCT Ultrasound should be consider in ALL melanomas or suspicious nevus Ultrasonography: COMMON Presentation Thicken elevated mass on B- scan Note the associated RD Specially important for documenting ANY peripheral lesion; which can t always be photo (can be used to follow for progression) Advantage of ultrasound over OCT Can penetrate through cataract Classic characteristic are recognized ú tumors > 3 mm in thickness, a combination of A- and B- scan can help Dx choroidal melanomas w > 95% accuracy Classic B- scan appearance is only observed in 20% pf cases Another classic presenta@on: Collar bucon; which is likely associated with RD Ultrasound: Mushroom w acoustic brightness on the tip DFE: Dome shape elevation is only noted if it break through Bruch s membrane/rpe 5

6 Other FEATURES include Orbital shadowing More classic Acoustic hollowness FA: limited in melanoma Dx The classic Double Circulation ú Although may be consider characteristics, it is NOT common Seen in lesion that broken through Bruch s Seen in LARGR TUMORS ú large caliber intra- lesion blood vessels that hyperfl There are a # of FA patterns, depending on tumor ú Size ú Associated pigment ú RPE integrity ú If tumor rupture through Bruch s Fundus auto Fl (FAF): LP observation Note far more LP observe in FAF than DFE Helps discern LP from other deposit (drusen) or pigments FA shows HYPOFl (due to blockage) associated with LP but pigmentary changes will also hypofl and mottle look is common hyperfl on FA may corresponds to the lesion that broke through bruch s (disruption/ missing RPE) or drusen 50% of melanomas show hyperfl on FAF What is the most common location of primary uveal melanoma to metastasize? Liver Lungs Bone Breast Brain Skin median survival for a hepatic metastasis: 15-20% at 1 year 10% at 2 years <1% after 5yrs, REGARDLESS OF TX Arch of Ophthalmol May (5):670 >25% of patients with ocular melanoma will develop metastases within 5 yrs s/p Dx Incidence of metastasis increase to 34% at 10yr COMS: Purpose These ú To were report pts with SITE initial of secondary dx choroidal CA melanoma development who were being evaluated for the presence of developing OTHER secondary tumors. ú Determine the time to Dx such CA THESE tumors were NOT associated METASTASES of the primary This is taken into account choroidal after melanoma. tx choroidal melanoma N = 2320 (40-60yo) pts with choroidal melanomas Evaluation took place while the pt was being tx for choroidal were evaluated with the following criteria at baseline melanomas (N= ~2000 pts w choroidal melanoma) f/u (- ) 5-16 melanoma yrs who metastasis had no secondary tumors at baseline (- ) primary cancer at baseline Follow up was 5-16 yrs 6

7 COMS: RESULTS ú 222 developed PRIMARY secondary tumors (~10%) ú MOST common cancers sites: 23% prostate 17% breast 12% lung ú Timeline 5 yr rate: 7.7% 10 yr rate: 14.9% Routine medical surveillance for development of secondary cancers, regardless of the size /tx of the choroidal melanoma is IMPORTANT for a lifetime SIDE BAR Routine exam finding " 54yo male in for routine exam " 20/20 vision " h/o skin melanoma & treated with interferon WHAT ARE WE LOOKING AT? Interferon induced retinopathy " Typical onset 1-5 mos s/p interferon tx " Often resolves w d/c Tx " More common in pts with known HTN/DM " Retinal vasculopathies include hemes & CWS Choroidal Melanoma l 53yo caucasian female l HTN and hypecholest. l Referred by OD l 20/20 OD 20/25 OS l Suspicious lesion OD l Sent for systemic w/u Post treatment l Systemic workup nega@ve for metastasis or other ca l Brachyplaque therapy l Vision to 20/50 post tx l CE and vision to 20/40 l Spread/mortality l Tumor configura@on l Histology l Spindle l Mixed l Epithelioid COMS 2001 ú Results: Plaque (I 125 Brachytherapy) was as successful as enucleation for medium size melanoma, having equivalent survival rate up to 12yrs s/p tx No significant difference in mortality rate No significant difference is presence of metastatic dz; when compared to enucleation Plaque (I 125 Brachytherapy) is the #1 tx for medium tumor >85% retain their eyes for 5yrs or more Collaborative Ocular Melanoma Study Group. #28 Ophthalmol 2006;124:

8 Radiation retinopathy (RR) nonproliferative >> proliferative Risk factors for the development nonproliferative RR There s 40% chance of dev NPRR s/p radiation tx tumor margin closer to the fovea HIGHER radiation dose rate ( >260 centigrays/hour) Risk factors for the development of proliferative RR à NVG There s a 10% chance of dev PRR s/p radiation tx DM Larger tumor (base >10 mm) PROPHYLACTIC AVT MAY SUPRESS DEVELOPMENT OF RR Anterior Segment may also be affected by radiation chronic dry eye eyelid abnormalities loss of eyelashes latissse epiphora from cannalicular damage Complications s/p radiation plaque tx When to enucleate? ú Enucleation (w/o pre- radiation tx) is reserve for large tumor COMS 2001: compared pre enucleation radiation vs SIMPLY just enucleation Pre- enucleation radiation treatment does not alter survival rate of patients with large melanoma within Enucleation is reserve when metastatic disease is high the Near/involving first 8 years the ON (regardless of size) Large tumors Diffuse melanoma Tumors with extraocular extension Collaborative Ocular Melanoma Study Group. #28 Ophthalmol 2006;124: Does aggressive surveillance have a (+) or (- ) impact of CA development? (Wen JAMA Ophthalmology Jan 2013) " Aggressive surveillance for pts with Hx of ocular melanoma appears to carry a HIGH RISK of secondary cancers development " This is associated with radiation exposure " A 10 yr ANNUAL f/u with CT of chest, abdomen, and pelvis was estimated to results in 0.9% lifetime cancer risk for men & 1.3% for women Genetic testing may help determine discern high risk of metastasize and need for aggressive surveillance " Younger patients and women are at higher risk " Risk of developing secondary cancer is as HIGH as 7.9% for a young (20 yo) female receiving a PET/CT scan q6m X 10 years. TODAY: Genetics and melanoma Testing perform with fine needle biopsy at time of surgery or if enucleated Gene expression profile (gene down regulation grwoth) Class 1 = relative low metastases (<10%) Thus although minimal, there is still chance of metastases Class 2 = very high metastases (90%) This gene expression also correlates with larger tumor diameter These classifications strongly predicted metastatic death with a 95% predictability based survival prediction at 8-9 yrs months s/p Dx Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64: ONH melanocytoma Note that melanocytoma is BENEATH vasculature & may causes elevated like appearance of ON Tumor displaces tissue but not invades it (not malignant) Unilateral 40-50yo DARKLY pigmented pt ú F>M Benign PIGMENT (melanocytic) growth (tumor) ú arises from melanocytes (pigment) and is a variant of the melanocytic nevus near or within the ONH Usually asymptomatic BUT associated findings may include: ú VFD are commonly noted (increase BS) but NOT affect VA ú Up to 30% can have (+) APD ú Fluid/hemes are rare but can occur in 10% of cases 1962, Zimmerman 8

9 What s the difference in presentations? What s your Dx? The 5yr mortality rate of an ONH melanoma is 75% & therefore, differentiate it from ON melanocytoma is CRUCIAL Management of ON melanocytoma includes follow up & photodocument Suspect choroidal melanoma over melanocytoma if: 2 nd complications (ONH edema or signs of leakage or symptomatic) Growth (<10% melanocytoma grow over a lifetime) CHRPE TUMORS that big would always be elevated Also note the lacunae CHRPE: focal area of RPE hyperplasia with more densely pack melanosomes Which belong to a CHRPE & which belong to nevus? Lacunae: window like defect Blackà gray Flat Round w discrete margins Note hypopigment ring (HALO) CHRPE often show thicker RPE with associated shadowing What s this? Younger than 30 yo Can a CHRPE transform to a malignant tumor? Look at symmetrical border Scalloped lacunae Halo around it Choroidal vasculature DDx Old toxo scar vs CHRPE RPE adenocarcinoma Intra- lesion NODULE(s) pedunculated, (elevated)à invades retina oval shaped May develop from CHRPE or in isolation 9

10 Gardner's syndrome has 2 part Congenital Grouped Pigmentation of the RPE (CGP- RPE) and 'pigmented ocular fundus lesions of familial adenomatous polyposis' (POFLs) Coleman P. Ophthalmic and Physiological Optics 2007 Bear track = group multiple 1. FAP= FAMILIAL ADENOMATOUS (glandular) POLYPOSIS Numerous intestinal polyps that have high propensity toward malignancy FAP may be asymptomatic at 1 st 2. Extra colonic manifestations (skeleton and various soft tissue manifestations) Osseous growth, skin cysts, dental abnormalities & multiple CHRPEs (80% of pt with FAP have this) Note the creamy mild elevation Because of life expectancy of pts with systemic CA has INCREASED; it s ocular complications are more common (affecting 8% of autopsy cases) Features displaying a Leopard-like appearance Choroidal metastasis (metastatic carcinoma TO THE choroid) Unlike primary choroidal melanoma; choroidal metastasis: Not as thicken (Doesn t assume the dome/mushroom shape) Creamier & WHITE More often associated with shallow RD & fluid More likely multiple and/or bilateral ~20% of presenting cases are bilateral Ultrasonography of choroidal metastases MILDLY elevated DIFFUSE choroidal thickness 90% of cases have a shallow RD A scan Moderate-HIGH reflectivity Internal disorganization metastasis melanoma 10

11 OCT can help with DDx Choroidal metastasis Choroiditis Unlike choroiditis; choroidal metastasis is thicker It is not associated with infectious/inflammatory disease Does NOT have associated inflammatory signs (vitritis, periphlebitis, exudation, old CRS, etc) More thicken (elevated) OCT may help Choroidal metastasis Choroiditis What is the most common PRIMARY location for a choroidal metastases (where did it come from)? Liver Brain Lung Heart Breast Breast for female Lung for males 6-9% of development Avg interval b/t Dx of primary tumor and uveal metastases is 3-6 yrs SIDE BAR: Tamoxifen l Tamoxifen is often used for treatment of breast cancer l <1% incidence of maculopathy l Common dose 20mg/d l Increased 40mg/d as needed l Most tx are only for a FEW yrs Of note, only >2/3 of pt with choroidal metastases have a hx of systemic CA Other sites include testis, gastrointestinal tract, kidney, thyroid, pancreas, and prostate A study by Heier (n= 135) found only 2 patients who developed retinal changes. Hence, since it is rare ophthalmic screening NOT required when low doses Rx Tamoxifen toxicity Perifoveal inner retinal refractile deposits (20/20): NLF & inner plexiform Incident related to TOTAL dose & hence, pts at risk for developing problems = HIGH dosage (> mg/d) Low dosage (10-20mg/d) X long- term The decision to D/C is not associated with deposits but rather with VL or macular complications. D/C meds associated with resolution of maculopathy but not of deposits Courtesy of Dr. J Autry OCT complications= CME or lamellar cyst 11

12 Tip of the iceberg Since choroidal metastasis occurs as a late onset of the associated cancer from a distal organ; it represents a poor prognostic in regards to pt s mortality rate Choroidal metastases are noted in 1/5 of pts who die from the associated CANCER (20%) within 1 yr Modalities geared to tx choroidal metastases Systemic Radiotherapy (including plaque) Chemotherapy Hormonal therapy Re-tipping the iceberg Choroidal metastases can further metastasize elsewhere (i.e. the brain) Astrocytic harmatoma l What is a Harmatoma: u Benign malformation resembling neoplasm, which same rate as surrounding tissue u Composed of elements normally found at site but which are growing is a disorganized mass Composition Astrocytes, calcium, assorted cellular debris. Literally, a mixed tumor Characteristic Patchy calcifications give it mulberry appereance OCT Intrinsic moth-eaten appearance Superficial retina show a hyper-reflective granular material; sparing RPE NO associated retinal edema/cme Systemic genetic syndromes to consider l Although astrocytic harmatoma may present in isolation, 2 conditions can be present: u Tuberous sclerosis (Bourneville's disease) u Neurofibromatosis Type 1 (von Recklinghausen NF or Peripheral NF) Systemically associated astrocytic harmatoma presented 1 st yr of life, multiple & bilateral; while acquired are unifocal, unilateral & appear in young adults 12

13 Choroidal osteoma Choroidal osteoma l Tumor arising from mature bone u Benign ossification of the choroid Choristoma (made up material that comes from elsewhere) u Rarely progresses l Young (20-30 yo) l Females l Typically asymptomatic u >80% have VA of 20/30 of better u May be associated with severe VL after 10yrs (20/200) but those have had associated complications: Subretinal fluid, CNV, PIL loss, hemorrhages l Usually stable Clinical presentation: Osteoma l Orangeà yellow large lesion u Plaque like u mottled surface with pigmentary changes u Margin are scalloped u Unilateral l Juxtapapillary u May involves ON Osteoma s OCT: large hyper reflective lesion under the retina. Note inner retina is preserve Tumor replaces normal choriocapillaris Dense hyperreflective mass with scalloped borders FA shows mottled (patchy) hyperfl pattern with more staining later stages l Complications (although rare) may include u CNV 30% of cases Diagnostic test is ultrasound l Note the HIGH peak refection on A-scan u calcification l Dense choroidal area with marked shadowing on b-scan E-scan shows reflectivity even with LOW gain Orbital shadowing 13

14 DDx: inactive posterior uveitis i.e. sepiginous choroidopathy CRS from posterior uveitis, trauma or WDS may be: Bilateral, more pigmentary changes & NOT ELEVATED (white represents atrophy revealing sclera NOT white bone infiltration) Tip of the iceberg There is no associated underlying SYSTEMIC disease REVIEWING the white ones thus far Presentation, age, laterality poor vision 8% Mulberry IF young/bilateral =?syndrome (NF/TS) Older pt, creamier Posterior pole Plaque rough elevation Young female Around the ON Leukocoria (50-60%) Strabismus (24 %) Orbital (<1%) Iris changing color (due to neo) Retinoblastoma Most common intraocular malignancy in childhood (neuroblastic tumor: arising from retinoblast) Up to 350/yr are reported in the US ú Encompasses 30% of ALL ocular malignancy ú Affects 1 out of 15,000 live births Mean age of Dx is mos (~18mons) 90% of cases are Dx before age 4-5 yrs ú 2/3 of cases are Dx by age 2 ú Rarely presents after age 6 but watch out for RETINOMAS White round domed-shape mass in pt <4yo Endophytic : grows toward the vitreous cavity (most common) appears globular w seeding into vitreous GROWTH TYPE Exophytic: under retina & more likely associated w subretinal fluid & RD 14

15 Laterality Family history Familial = known family Hx (only 6% cases) Sporadic ú no known FHx ú Most common presentation Unilateral Most presentations Bilateral <30% Germline May be multiple DNA testing Heritable (Germline mutation): (+) DNA genetic testing 40% of cases Often bilateral & even multiple Of interest many (+)DNA germline have NO (+) FHX seeding Non-heritable ú Unilateral ú Most common presentation (60% of cases) High reflectivity noted in A-scan (calcification) B-scan shows Solid tumor the RETINA w vitreous seeds Prompt Detection Smooth NLF & RPE hyperreflective solid lesion WITHIN the retina Early detection = better prognosis 90% of affected children are saved by early detection ú prompt tx of retinoblastoma decreases odds of intracranial neuroblastic tumor CNS tumor include pinealoblastoma & parasellar region tumor Dx typically made <5 yo 15

16 Trilateral retinoblastoma Bilateral retinoblastoma + pineoblastoma The retinoblastoma that is at HIGHEST risk for developing an intracranial tumor are. TIME TO ALSO CONSIDER MRI BRAIN IF: MRI neuro si/s: ú Bilateral seizures, ú HA, Have somnolence a (+)FHx in children (lethargic like) ú &/or (+) DNA for germline The management for any of these presentations include: screened with brain MRI q6m after dx of retinoblastoma until age 4-5 Tumors: A review l Look at the color l Compare the findings to the other eye l Dx test may help confirm the Dx u Ultrasound, FA, OCT, etc l Remember that it may be the tip of the iceberg u you are saving vision, you are saving eyes & most important you may be saving LIVES! 16