Moran CORE

• Iris pigment epithelial cysts -encompass both layers of iris and produce localized stromal elevation. May need B-scan or trans-illumination to see.
• Iris pigment epithelial proliferation results from congenital or acquired (trauma/surgery) –composed of plaques of pigment epithelium –black, velvety color.
  • Juvenile xanthogranuloma -yellow/grey iris lesions with orange skin
  • Lesions in 1st yearof life.
  • Assoc. 1. with spontaneous hyphema
  • Secondary glaucoma
  • Diffuse granulomatous reaction with lipid filled histiocytes and touton giant cells Regress spontaneously
• Leiomyoma
  • localized or diffuse, pedunculated or flat
  • Electron microscopy required to differentiate from amelanotic spindle cell melanoma
• Leukemia -very rare
  • Nodularor diffuse milky lesions with intense hyperemia.
  • Pseudohypopyon
  • Iris loses architecture and becomes thickened.
• Lisch Nodules
  • one of the diagnostic criteria for NF-1
  • Multiple flat or raised tan to brown lesions
  • Composed of collections of nevus cells
• Malignant melanoma
  • Nodular of flat –usually peripheral
  • 80% inferior + inferotemporal
  • May have nutrient vessel, satellite pigmentation
  • Pupil may dilate irregularly
• Melanocytosis
  • Unilateral, heterochromia irides
  • May have oculodermal form with eyelid + brow involved
  • Has malignant potential

• Retinoblastoma
  • White foci on iris surface or in angle
  • May have pseudohypopyon
  • Retinoblastoma present in posterior chamber
• Tapioca Melanoma
  • Often associated with unilateral glaucoma.
  • Tapioca-like nodules over part or all of iris
• Metastatic Carcinoma
  • Gelatinous to white vascularized nodules on iris surface.
  • May be associated with anterior uveitis, glaucoma, rubeosis, and hyphema.

Iris Nevus:

 

17.01 External slit lamp photo

 

17.02 Spindle nevus

 

17.03 Borderline spindle nevus

 

17.04 Epithelioid nevus

• Darkly pigmented lesion of iris stroma
• minimal distortion of normal architecture
• circumscribed > typically nodular + discrete
• diffuse > may involve entire sector or even entire iris
• increased incidence in NF –1
• most common in Caucasian background (97%)(1)
• ABCDEF guide for risk factors 1–risk of nevus transformation to melanoma increases for the following:
  • A –age –younger age is higher risk
  • B –blood –hemorrhage is common in melanoma
  • C –clock hour inferiorly –inferior location is higher risk
  • D –diffuse configuration –diffuse nevus more likely for malignant transformation
  • E–ectropion –ectropion uvea increases risk
  • F –feathery margin

Iris Melanocytoma:

• Dark pigmented brown lesion –may have granular “mound of black sand” appearance.(1)
• Usually stable and does not require intervention
• May have spontaneous necrosis –which can liberate pigment into anterior chamber and cause glaucoma.
• In one series of 47 patients, 48% showed mild growth and 63% showed new tumor seeds, but none (0%) showed malignant transformation(4).
  

Iris Melanoma:

 

17.05 External slit lamp photo

 

17.06 Spindle melanoma

 

17.07 Epithelioid melanoma

 

17.08 Mixed melanoma

Nick’s Tips: When small iris melanoma may be impossible to differentiate from nevus –may consider biopsy done through clear cornea.

• Risk of metastasis is about 3%,(5) much less commonly fatal than other choroidal melanomas possibly due to
  • Earlier diagnosis and usually smaller at diagnosis
  • Most commonly spindle cell type(over 50%)
  • May have other unique features
• Least common site of primary uveal melanoma (about 3-10%).(6)
• Associated with: (6)
  • Light iris color
  • Inferior location
  • Average age 40 years old (younger than choroidal melanoma (age 50))
• May appear circumscribed (melanotic nodule) or diffuse (heterochromia), with diffuse having a somewhat poorer prognosis.
• Histopathologic features:
  • Typically spindle uveal melanoma cells –
    • Plump nucleus,
    • Eosinophilic nucleolus visible,
    • Mildly coarse chromatin
• Some are mixed cell type (combination of spindle and epithelioid
• Epithelioid –
  • Abundant eosinophilic cytoplasm and distinct cell borders
  • Large nucleus
  • Central nucleolus
  • Larger and more pleomorphic than spindle cells.
• Signs of iris melanoma:
  • Ectropion iris
  • Prominent Vascularity
  • Sectoral cataract
  • Secondary glaucoma
  • Progressive growth
  • Extrascleral extension
  • Seeding of angle
  • Large size
  • ¾ of iris melanomas involve inferior iris
  • Unilateral glaucoma
  • Spontaneous hyphema
• Treatment
  • Excision
  • Brachytherapy
  • Proton beam

Iris Cysts:

 

17.09 Iris stromal cyst

• Imaging:(2)
  • Ultrasound (UBM) –better at imaging posterior wall and overall imaging of structure
  • Anterior Segment OCT –better at imaging anterior surface of lesion
• Types of iris cysts
  • Stromal cysts
    • may be congenital or acquired
    • usually smooth, translucent mass on in in the iris
    • may have debris inside cyst
    • may rupture –can cause iritis or glaucoma if ruptured
    • Congenital stromal cysts in children under age 10 tend to be more aggressive and may have poor visual outcome.
    • Treatment –may surgically remove or may aspirate cyst and sclerose with absolute alcohol.(3)
  • Pigmented epithelial cysts
    • Usually asymptomatic
    • Darkly pigmented –arising from posterior surface of the iris
    • May resemble ciliary body melanoma or iris pigmented epithelial adenoma, clinically.
    • UBM and anterior segment OCT may help demonstrate cystic nature of lesion.

Nevus of choroid / ciliary body

 

17.10 Fundoscopic photoof nevus

Nick’s Tips: Although no single feature differentiates a malignant melanoma and a choroidal nevus, virtually all melanocytic tumors greater than 3mm thick are melanomas and virtually all melanocytic lesions less than 1mm thick are Nevi.

• Choroid nevus –7% of population –flat or minimally elevated
• May be amelanotic or grey-black
• Differential diagnosis of a pigmented fundus Lesion
  • Nevus
  • Melanoma
  • Atypical disciform scar
  • Suprachoroidal hemorrhage
  • RPE hyperplasia
  • CHRPE
  • Melanocytoma
  • Choroidal osteoma
  • Hemangioma with RPE changes
  • Metastatic tumor with RPE changes
• Risk of melanoma
  • Increased with thickness > 1 mm
  • Increased with diameter > 10mm
  • (<10mm almost always benign)
  • Visual symptoms
  • Orange pigment
  • Subretinal fluid
  • Large size >1mm thick, >10mm diameter
  • Juxtapapillary
  • Absence of drusen or RPE changes
  • Hot spots on FA
  • Homogeneity on ultrasound
  • Enlargement

Melanocytoma:

 

17.11 Ciliary body melanocytoma

• Rare, large polyhedral shaped cells with small nuclei + melanin.
• May seed A/C causing glaucoma
• In choroid, they appear like nevis or melanoma on exam
• May undergo malignant changes.
• If growth is documented, treat as malignant.

Melanoma of ciliary body/choroid:

 

17.12 Ciliary body melanoma

 

17.13 External slit lamp photo

 

17.14 Gross cross-section of globe

 

17.15 Tumor arising from ciliary body

 

17.16 Tumor arising in ciliary body coming into trabecular meshwork

 

17.17 Choroidal Melanoma

 

17.18 Spindle cell A choroid

 

17.19 Spindle cell B choroid

 

17.20 Epithelioid choroid

 

17.21 Mixed melanoma choroid

Nick’s Tips:

Histopathology of Choroidal Melanoma/Nevus:

• Six types:
  • Spindle nevus
  • Spindle nevus with plaque
  • Borderline spindle nevus
  • Spindle melanoma
  • Epithelioid nevus
  • Epithelioid melanoma
• Prognosis from histological features –poor outcomes due to metastasis via scleral emissary channels
  • Pure spindle B –good prognosis
  • Mixed is intermediate prognosis
  • Epithelioid is poor prognosis

Clinical Features of Choroidal Melanoma

• Most common primary intraocular malignancy in adults 6-7 cases per million.
• Primary affects patients aged 50’s-60’s
• Risk factors:
  • Light complexion, light irides
  • Ocular melanocytic conditions
  • Melanosis oculi, oculodermal melanocytosis
  • Genetic predisposition (dysplastic nevus syndrome)
  • Cigarette smoking
• May be clinically silent + large when detected.
• Symptoms may include
  • Vision loss or decreased vision
  • Changes in or decreased visual field
  • Photopsias
  • May have no symptoms
• Appearance:
  • May rarely erode through sclera or iris + become visible on external exam
  • Initial sign of ciliary body melanoma may be dilated episcleral sentinel vessels.
  • Ring Melanoma → 360° -180° melanoma of ciliary body.
  • Pigmented, elevated dome shaped.
  • May be amelanotic to dark brown.
  • May erupt through Bruch’s membrane + make mushroom shape.
  • Orange pigment clumps may form @ RPE level.
  • Serous detachment of retina is common
  • Neovascularization, hemorrhage, lens subluxation are late complications
  • Vitreous hemorrhage only if penetrated through Bruch’s
• Diagnostic Evaluation:
  • Indirect ophthalmoscopic evaluation-#1 technique.
  • Gonioscopy –best method for establishing anterior involvement
  • High-frequency ultrasound for iris + ciliary body evaluation
  • B-scan u/s →for tumor measurement, extrascleral extension
  • A-scan u/s →for internal reflectivity (characteristic low internal reflectance –homogenous)
  • Transilluminationmay help identify tumor
  • Wide angle fundus photography.
  • FA does NOT have characteristic appearance.
  • CT + MRI may help in opaque media
• Differential diagnosis:
  • choroidal nevus: usually flatter + smaller
  • ARMD with pigmented scar –fluorescein angiographypathognomic –hemorrhage rare in melanoma
  • CHRPE –well defined, flat dark lesion-histology → tall melanin containing RPE cells that are histologically identical to bear tracks.
  • Melanocytoma of the optic disc.
    • Has minimal malignant potential
    • Lesion is located peripapillarily.
    • 10% will show growth over 5 years
    • May produce vision and visual field defects due to nerve fiber layer disruption
  • Suprachoroidal Detachments:
    • May be hemorrhagic orserous.
    • Associated with hypotony.
    • Often dome shaped, associated with breakthrough vitreous hemorrhage.
    • Usually located in multiple quadrants
    • Usually treated with observation
  • Choroidal Osteoma:
    • Benign bony tumors. Yellow to orange, well defined
    • Arise from juxtapapillary choroid
    • Adolescent to young adults
    • High amplitude echo on u/s from bony plate with shadowing behind lesion.
    • Calcification on CT scan.
    • Typically slow growing over years
    • May affect vision if in macula or nearby
    • Etiology unknown, may be related to low-grade inflammation
    • Subretinal neovascularization common

Classification of Melanomas:

Nervus	<5mm diameter	<2mm thick
Small	5-10mm	2-3mm thick
Medium	10-15mm	3-5mm
Large	15-20mm	5-10mm
Extra Large	>20mm	>10mm

 

• Metastasis up to 50% at 25yrs, 25% at 5yrs, 34% at 10yrs (COMS Study)Less than 2% have clinically detectable metastatic disease at time of diagnosis. Median survival less than 6months with metastatic disease.Liver 1st site of metastasis, 89% on clinical exam 100% on autopsy. Lung, 24% on clinical exam 50% on autopsy; skin, 12% on clinical exam 50% on autopsy; bone possible later 17% on clinical exam 50% on autopsy.
  
  • Clinical Evaluation: (yearly follow-up)
    • Liver ultrasound
    • Liver function tests (LFTs)
    • Chest X-ray (low yield)
    • If any are positive tests, then Tri-phasic liver CT, CT or MRF of chest + abdomen.
    • Metastases can develop up to 20 years after treatment.
  • Treatment: little evidence of natural history exists.
    • If metastasis found, then enucleation is NOT appropriate.
    • Much of the treatment protocols were developed from the results of the COMS trial –a randomized prospective treatment study of choroidal melanoma.
    • Methods of treatment depend on
      • Size, location, extent
      • vision of affected + fellow eye
      • age + general health
  • Treatment Protocols:
    • Observation:
      • small melanoma <1mm thick
      • Elderly or otherwise short life expectancy
    • Enucleation: Gold-standard for treatment
      • Does NOT disseminate tumor secondary to manipulation.
      • Appropriate for all medium to extra-large tumors
    • Brachytherapy: most common method of treating uveal melanoma.
      • High dose, localized radiation. Usually I125, Ruthenium106 plaques
      • Local control rates >96%
      • Optic neuropathy + radiation retinopathy in 50%-Location + dose dependent complications
  • Charged particle radiation: proton beam.
    • Requires tantalum localization clips.
    • Up to 98% local control. Increased radiation dose to anterior segment.
  • External Beam Radiation: can be used in conjunction with enucleation or brachytherapy.
  • Other Alternative Treatments:
    • Photoablation + hyperthermia → subretinal fluid treated with grid laser: leads to increase in tumor growth due to rupture of Bruch’s membrane
    • Transpupillary Thermotherapy –associated with decrease in tumor volume.
    • Cryotherapy –not thought to be effective
    • Transcleral diathermy –contraindicated–provides route for extrascleral extension
    • Surgical excision: may have success, but difficult + margins are very important.
    • Chemotherapy: Not effective for treatment, but may be palliative
    • Immunotherapy: under investigation
    • Exenteration: rarely employed, but may be used in cases with extrascleral extension.
  • Prognosis: 5yr mortality:
    • 50% for large
    • 30% for medium
    • 12% for small
  • Risk factors for mortality:
    • Large tumor
    • Growth
    • Anterior tumor location
    • Extraocular extension
    • Older age
    • Tumor regrowth after ocular conservation therapy
    • Rapid decrease in size after globe conserving treatment
    • Juxtapapillary tumors.
    • Histopathological Features associated with increased mortality
      • Epithelioid cells
      • High mitotic index
      • Complex microvascular patterns
      • Large nuclei
      • Tumor infiltrating lymphocytes
      • Monosomy 3
      • Trisomy 8
  • Collaborative Ocular Melanoma Study.
    • 1003 patients with large or extra-large choroidal melanomas
      • Greater than 16mm diameterand/or greater than 10mm thick
      • Comparedenucleation to enucleation + external beam
      • 5-yr survival 57%with enucleation versus 62% with external beam
      • No improvement with radiation over enucleation alone.
    • 1317 patients with medium-sized choroidal melanoma
      • Tumor size: 6mm-15mm diameter and/or 2.5-10mm thick. Compared enucleation with brachytherapy
      • No difference in mortality (18% for enucleation and 19%for brachytherapy)
      • 43% had visual acuity worse than 20/200 with brachytherapy
      • Small ↑ in mortality with tumor recurrence
    • 204 patients with small choroidal melanoma
      • 4-8mm wide x 1-2.5mm thick
      • Mortality 1% at 5 years
    • COMS Study risk factors for growth
      • Increased thickness + diameter @ presentation
      • Orange pigment
      • No drusen or RPE changes
      • Pinpoint hyperflourescence on FA
        

  Pigmented Epithelial Tumors of Uvea + Retina:

  • Adenoma:
    • (benign) very rare
    • Oval, deeply melanotic tumors arising abruptly from RPE
    • Rarely undergo malignancy change.
  • Adenocarcinoma:
    • very, very rare
    • Malignantpotential very low.
  • Ciliary Cysts
    • Opacified ciliary cysts associated with multiple myeloma and macroglobulinemia

  Fuchs’ Adenoma

   

  17.22 Fuch’s adenoma

  • • Usually incidental finding @ autopsy.
    • Glistening white irregular tumor from ciliary crest.
    • Benign proliferation of non-pigmented epithelium
  • Acquired Hyperplasia: RPE + ciliary pigmented epithelium may
    • Proliferate in response to trauma or surgery.
    • may mimic choroidal melanoma
    • Treatmentis to observe.
  • Combined Hamartoma:
    • Rare–occurs at the disc margin. Dark pigmented, minimally invasive lesion
    • Proliferation of RPE, glial, + blood vessels
    • May cause retinal traction.
    • May have more or less pigment
    • May be mistaken for melanoma.

  Angiomatous Tumors

  Choroidal Hemangioma

  • Circumscribed choroidal hemangiomas are not associated with systemic disorders
  • Red/orange tumor, often in macula
  • Often produces secondary retinal detachment
  • Often affect overlying RPE with degeneration of outer retina.
  • Differential diagnos is
    • Amelanotic choroidal melanoma
    • Choroidal osteoma
    • Metastatic carcinoma
    • Granuloma of choroid.

  Diffuse choroidal Hemangioma associated with Sturge –Weber Syndrome

  • Diffuse reddish-orange thickening of retina
  • Tomato catsup fundus.
  • Retinal detachmentcommon
  • Glaucoma common.
  • FA shows large choroidal vessels, in pre arterial + arterial phases and late staining of tumor. NOT pathognomonic. U/S shows high internal reflectivity, acoustic heterogeneity. No shadowing. CT scan can be helpful in differentiating from osteoma. Treatment:
    • observation if asymptomatic
    • Serous detachment (including fovea) → photocoagulation
      • Treating withlight laser to adhere retina + ↓ serous fluid.
      • Recurrent detachments common.
      • PDT → to entire lesion may involute tumor + ↓ fluid.
      • Brachytherapy, Proton Beam, Gamma Knife have been used to involute tumor as well.
      • Periocular + intraocular avastin is being investigated.

  Retinal Angiomas:

  Capillary Hemangioma

   

  17.23 Capillary hemangioma in Von Hippel –Lindau syndrome

  • Rare, autosomal dominant (1 in 40,000)
  • Diagnosis at age 10-30.
  • Orange/red tumor arising in retina with tortuous vessels.
  • Subretinal exudates common + often in fovea.
  • Exudate detachment common.
  • “Von Hippel disease”
    • familial in 20%
    • Bilateral in 50%
  • Von Hippel–Lindau Syndrome choroidal hemangioma with associated with cerebellar hemangioblastoma
  • Genetics
    • Gene located on chromosome 3
    • Associated tumors
      • Retinal capillary hemangioma
      • Cerebellar hemangioblastoma
      • Renal Cell Carcinoma
      • Pheochromocytoma
    • Genetic screening can help determine risk of tumors,
  • FA shows feeding arteriole, massive network + draining venule.
  • Treatment:
    • Photocoagulatesmall lesions.
    • Cryotherapy for larger, peripheral lesions.
    • Penetrating diathermy for very large lesions.
    • Avastin isbeing investigated.

  Cavernous Hemangioma

   

  17.24 Cavernous hemangioma

  • Uncommon, cluster of grapes lesion.
  • Generally not associated with exudates.
  • Small hemorrhages + gliosis may appear on surface.
  • May occur on optic disc.
  • FA is diagnostic–fills slowly fluorescein + RBCs separate.
  • No vitreous leakage (unlike Coats Disease or capillary hemangioma)
  • No treatment necessary for cavernous hemangioma.
  • Composed of dilated, thin walled vessels, interconnected

  A-V malformation

  A-V malformation:

  • Racemose Hemangioma (congenital retinal A-V malformation)
  • Range from small vascular communication near disc or periphery
  • To large tangle of tortuous vessels throughout fundus.

  Wyburn-Mason:

  • Racemose hemangioma + midbrain A-V malformation.
  • Associated A-V malformations possible in orbit+ mandible

  Retinoblastoma

   

  17.25 Retinoblastoma

   

  17.26 Gross cross-section globe of RB

   

  17.27 Exophytic growth pattern of RB

   

  17.28 Endophytic growth pattern

   

  17.29 Necrosis

   

  17.30 Dystrophic calcification

   

  17.31 Flexner-Wintersteiner rosettes

   

  17.32 Alcian blue stain

   

  17.33 Fleurette

   

  17.34 Vitreous seeding

   

  17.35 Tumor invading optic nerve

  Nick’s Tips: The differential diagnosis of leukocoria in a child and specifically the details of retinoblastoma is one of the most high yield study subject for the Boards. In addition, this material may enable you to save a child life someday.
  

  Retinoblastoma:

  • #1 most common primary malignancy of childhood.
  • 2nd most common primary malignancy (behind uveal melanoma) in all age groups.
  • 1 in 14,000-20,000, 300 new cases/year in USA.
  • No gender predilection
  • 30% to40%bilateral.
  • Age @ diagnosis:
    • Family history of known retinoblastoma→ 4months
    • Bilateral disease → 14 months
    • Unilateral disease →24 months
    • 90% by age 3.
  • Genetics: mutation in retinoblastoma tumor suppressor gene.
    • 6% familial
      • 98% chance of germline mutation in bilateral disease.
      • Children of retinoblastoma survivor have 45% chance of having retinoblastoma (50% transmission, 90% penetrance)
    • 94% sporadic.
      • About 60% have unilateral disease
        • No germline mutation
        • Most have unifocal tumor
      • 40% have new germline mutation + multifocal disease.
    • About 95% chance of finding germline mutation with genetic testing.
  • Presentation:
    • Leukocoria = most common presentation
    • Strabismus + ocular inflammation also possible.
  • Clinical Appearance
    • Begins as grey/translucent intraretinal tumor with dilated feeder vessels
    • Becomes chalky white as calcification occurs.
    • Serous retinal detachment may occur as tumor grows + cause ↓ vision + difficulty visualizing tumor.
    • Exophytic tumors: grow beneath retina → retinal detachment
    • Endophytic tumors:
      • Grow on retinal surface into vitreous.
      • Vitreous seeding more common
      • May seed Anterior chamber leading to
        • Pseudohypopyon
        • Rubeosis + secondary to glaucoma in 50%
    • Diffuse –infiltrating retinoblastoma:
      • Appears like intermediate uveitis with diffuse vitreous cells,
      • Poor view of retina.
    • Metastatic
      • Most common metastasis is through direct extension via optic nerve.
      • May extend into subarachnoid space.
      • May also erode through sclera or emissary veins into orbit.
      • In A/C, may invade trabecular meshwork + lymphatics.
      • Metastatic to:
        • Skull bones, distant bones
        • Brain, spinal cord
        • Lymph nodes (preauricular/cervical)
        • Abdominal viscera
    • Clinical Exam:
      • Need exam under anesthesia with scleral depression.
      • Document clearly location + size of multiple tumors.
      • Ultrasound may show calcifications
      • MRI is imaging modality of choice for globe, ON, brain.
      • Systemic evaluation not necessary if no signs of extraocular extension.
      • LP if extensionvia ON thought to have occurred
      • Examine siblings + parents
    • Differential Diagnosis of Leukocoria:
      • Retinoblastoma
      • Coats disease
      • Astrocytic hamartoma –tuberous sclerosis
      • Retinal capillary hemangiomatosis
      • Granulomas (especially associated with nematode endophthalmitis) -toxocariasis
      • Coats
      • Persistent fetal vasculature
      • Ocular toxocariasis
      • Retinopathy of prematurity
      • Retinal detachment
      • Coloboma
      • Myelinated nerve
      • Toxoplasmosis
      • Retinal dysplasia
      • Trisomy13 → cartilage in ciliary body
      • Norrie’s disease
      • Retinoschisis
      • Cataract (torch, congenital)
      • Cyclitic membrane
      • Medulloepithelioma
      • Incontinenti pigmenti

  Coats Disease:

   

  17.36 Fundoscopic photo

   

  17.37 Gross cross-section globe

   

  17.38 Telangiectasic vessels leak into retina and under retina

   

  17.39 Processed specimen leaving sickle shaped cholesterol plaques

  • male>female (10:1)
  • poor visual prognosis
  • Unilateral retinal telangiectasias, yellow exudates.
  • No distinct mass, (cholesterol rich sickle shaped spaces)
  • Fluid leakage may lead to serous retinal detachment which may be large
  • Ultrasound documents absence of retinal tumor.
  • Treat with laser or cryo of vascular anomalies to decrease serous detachments

  Persistent Fetal Vasculature (Persistent hyperplastic primary vitreous):

   

  17.40 External slit lamp photo

   

  17.41 Mass in the lens pulls and contracts ciliary processes forward.

   

  17.42 Remnant hyaloid artery

   

  17.43 Bergmeister papillae

   

  17.44 Gross cross-section glob

   

  17.45 PHPV

   

  17.46 Remnant Hyaloid artery

  • Typically recognized in 1st few weeks of life
  • Unilateral in 2/3
  • Associated with
    • Microphthalmos.
    • Shallow anterior chamber
    • Hypoplastic iris
    • Retrolenticular mass of fibrovascular tissue
  • Vascular stalk may be seen arising from nerve.
  • May have closed funnel retinal detachment
  • Ultrasound shows no tumor, short axial length +/-calcification
  • Treatment is vitrectomy/lensectomy.

  Ocular Toxocariasis:

 

 

17.47 Toxocariasis

• • Most patients have a history of soil ingestion or exposure to puppies.
  • Posterior mass + peripheral granulomas + uveitis.
  • Ultrasound shows vitritis, granuloma, retinal traction, NO calcification
• Astrocytoma: (astrocytic hamartoma)
  • Small, white, glistening tumor of nerve fiber layer
  • Sometimes large, mulberry appearance with calcification.
  • Usually arise from optic disc (termed “giant drusen”)
  • Common in tuberous sclerosis + may occur in neurofibromatosis
  • Usually ∅assoc. with phakomatosis.
• Retinocytoma: clinically indistinguishable from retinoblastoma
  • Histologically benign.
  • Same genetic implications as retinoblastoma
  • Unclear developmental biology.
• Reece-Ellsworth classification of intraocular retinoblastoma.
• Predicts eye preservation when treated with external beam radiation.

	A	B
Group I (very favorable)	solitary tumor <4DD	multiple tumors
II	4-10DD	multiple 4-10DD
III	at equator or anterior	>10DD posterior
IV	multiple tumors, some >10DD	anteriorto ora serrata
V(least favorable)	massive tumor > ½ retina	vitreous seeding

International Classification

A	Small(<3mm)	>3mm from fovea	>1.5mm from optic nerve
B	(>3mm)	confined to retina
C	Localizedvitreous or subretinal seeding.	<6mm from tumor
D	Diffuse vitreous or subretinal seeding.	>6mm from primary
E	No visual potential or tumor in anteriorsegment, in or onciliary body, neovascular glaucoma,vitreous hemorrhage, phthisical eye, orbital extension/proptosis.

 

• Trilateral Retinoblastoma:
  • bilateral intraocular retinoblastoma + ectopic intracranial retinoblastoma.
  • Ectopic foci usually in pineal gland. (pinealoblastoma)
  • Occurs in 2-5% with germline mutation.
  • Usually pineal
  • blastoma presents years after retinoblastoma, but may present before.
  • Often show Flexner-Wintersteiner rosettes on histology.
  • Embryological evidence for photoreceptor differentiation in pineal glando
  • All retinoblastoma patients should undergo neuroimaging.
  • Serial MRI with and without contrast = best (No radiation exposure)
  • Decreased incidence of trilateral retinoblastoma with chemo –may be prophylactic.
  • Median survival 8 month with CNS involvement.
• Prognosis:
  • 95% survival if contained in eye
  • Less than 50% survival if extraocular spread.
• Treatment:
  • Goals
    • #1 preserve life,
    • #2 preserve eye,
    • #3 preserve vision.
  • Enucleation: definitive treatment. Usually enucleate if any of the following:
    • Tumor >50% of eye
    • Orbitalor ON involvement suspected
    • Anterior segment involved
  • Chemotherapy:
    • carboplatin, vincristine, etoposide, cyclosporine
    • IV treatment Q3-4 weeks in 4-9 cycles.
    • Decrease tumor volume + finish treatment with laser, cryo, radiation.
  • Periocular Chemo: in phase 1 + 2 trials, shows promise.
  • Photocoagulation + hyperthermia:
    • May kill tumor blood supply
    • Cytotoxic effect of heat.
    • Small tumors.
  • Cryotherapy
    • Small tumors <10mm diameter, <3mm thick.
    • Anterior location (laser for posterior)
    • Repetitive treatment+ close follow up.
  • External Beam:
    • retinoblastomais radiation responsive.
    • 4,000 –4,500 cGy over 4-6 wks.
    • Typically are bilateral not amenable to cryo or laser.
    • 85% of globes retained.
    • Visual function limited only by tumor location and secondary complications.
  • Concerns:
    • Retinoblastoma mutation associated with lifelong increased risk of osteosarcoma
    • Risk of osteosarcoma is exacerbated by exposure to external beam radiation
    • Midface hypoplasia
    • Cataract
    • Radiation optic
    • Neuropathy + other radiation side effects.
  • Combination therapy may decrease radiation and its secondary complications.
• Brachytherapy: salvage therapy for some eyes
• Primary treatment for amenable eyes with small-medium tumors.
• Adenovirus targeted gene therapy in trials → makes tumor susceptible to ganciclovir –via Thymidine Kinase transfection
• Spontaneous Regression:
  • May undergo complete necrosis + regression.
  • Sometimes seen in phthisical eyes.
  • Vitreous filled with islands of calcified cells in mass of fibrovascular connective tissue.
  • Associated with exuberant proliferation of RPE + ciliary body
  • Ghost contours of tumor cells.
• Prognosis:
  • Survival greater than 95% with access to modern care.
  • Extraocular extension is the most important poor prognostic factor
  • Bilateral diseasemay have decreased survival secondary to optic intracranial foci
  • Bilateral retinoblastoma leads to increased incidence of other tumors
  • Mean time = 9 years
  • 26% develop another tumor in 50 yrs.
  • External beam radiation decreased latency and increased head + neck tumors.
  • Most common secondary tumor = osteogenic sarcoma
  • Also pinealoma, brain tumor, melanoma, sarcoma, primitive tumors
    • 10-20% will develop tumor in 20 years
    • 30-40% will develop 3rd tumor in 30 years
    • Survival <50% in those who develop 2° osteogenic sarcoma.
      

Secondary Tumors

Metastaticintraocular tumors:

 

17.48 Fundoscopic photo

 

17.49 Lung cancer metastasized to choroid

Nick’s Tips:

• Metastases are the most common intraocular tumors in adults
• Metastases are the most common orbital tumors in adults

Mets to Eye

Males	Females
Lung 40%	Breast 68%
Unknown 29%	Lung 12%
GI 9%	Unknown 12%
Kidney 6%	Others 4%
Prostate 6%	GI 2%
Skin 4%	Skin 1%
Others 4%	Kidney<1%

 

• Choroid is 10-20 x more likely location for metastases, due to higher blood supply than iris or ciliary body
• Metastases to the retina + optic disc rare
• Bilateral in 20-25%
• Metastases are often yellow/white/grey, may have RPE changes
• Metastases to the posterior pole may cause decreased visual acuity
• Rarely break through Bruch’s membrane
• May cause retinal detachment over tumor
• Necrosis + uveitis possible
• Diagnosis:
  • FA pattern of double circulation + early filling seen in choroidal melanomas is rare in metastatic tumors
  • Ultrasound is helpful,
    • A-scan shows moderate to high reflectivity (melanoma = low)
  • Fine needle aspiration biopsy may help, but metastases may be too poorly differentiated to identify.
• Metastases to retina are very rare:
  • Appear as white, non-cohesive lesions
  • May appear similar to cotton wool spots
  • May vitreous seed + appear like retinitis.
• Previous diagnosis versus unknown cancer diagnosis:
  • Breast cancer
    • 70-90% with metastatic ocular or orbital breast tumor to uvea have a history of breast CA diagnosis + treatment.
    • If no prior diagnosis of breast cancer, then refer for breast exam
  • Lung cancer
    • Lung metastases often do not have prior diagnosis.
    • Poor prognosis if uveal metastasis. Mean survival 1-67 mo
• Prognosis: Depends on primary tumor.
  • Lung + GI is worst prognosis
  • Carcinoma+ breast cancer is better prognosis
• Treatment: depends on many factors
  • Goals
    • Maintain vision
    • Palliate pain.
  • Types:
    • Systemic chemo or hormone treatment
    • Laser, cryo, beam radiation, etc….
    • Enucleation with unrelenting pain.
• Avenue of entrance to the orbit or globe
  • Hematogenous inoculation is by far the most common
    • Breast, lung, GI, and others
  • Direct intraocular extension is rare because the sclera is a good barrier.
    • Squamous cell carcinoma from conj. = most common
    • Conj. Melanoma
    • Basal cell of eyelid possible

Lymphomatous Tumors

Intraocular lymphoma:

 

17.50 Lymphoma

• Type:
• Almost always Non-Hodgkin, B-cell, large cell.
• T-cell = rare.
• May invade any part of eye/orbit.
• Source:
• Most common = primary CNS lymphoma (25% have intraocular involvement) Vitreous + retina involved
• Rarely Systemic/visceral/nodal lymphoma: usually uveal tract + choroid.
• Making the diagnosis
• Any bilateral or chronic uveitis age over 50 should consider lymphoma.
• Diffuse vitreous cells, headlight in fog appearance.
• Complete neuro exam will be positive of deficiencies in 10% of patients
• 60% will have central nervous system involvement –should do
• CT
• MRI
• LP
• Diagnostic vitrectomy.
• Pathology
• Flow cytometry
• PCR
• Immunohistochemical stains
• Treatment
• Limited by blood-ocular barrier.
• Irradiation with external beam –tumor invariably reoccurs.
• Intraocular methotrexate → good response, low recurrence
• CNS treatment by oncologist
• Prognosis: poor, requires close f/u

Uveal Lymphoid Infiltration:

• Uveal Lymphoid Infiltration: (reactive lymphoid hyperplasia) –unknown etiology
• May occur at any site. –benign lymphoid infiltration
• Painless progressive vision loss
• Diffuse amelanotic thickening of choroid
• Exudative retinal detachment+ glaucoma in 85%, proptosis 15% due to orbit infiltration
• Treatment: high dose steroid, fractionated radiation
• Excellent prognosis

Leukemia

• Ocular involvement common –up to 80% on autopsy
• Up to 40% at diagnosis.
• Retinal lesions most commonly found, choroid is most common site.
• Choroid may act as sanctuary for leukemic cells
• Eye may be 1st sentinel of reactivation
• Ultrasound may be better than indirect ophthalmoscopy.
• May involve iris with small nodules @ pupil margin or diffuse thickens
• May have pseudohypopyonor 2° glaucoma.
• Retinal findings include:
  • hard exudates
  • CWS
  • Pseudo-Roth spots.
  • Yellow deposits in retina,
  • Grey nodules in CML
  • Perivascular streaks
• Vitreous involvement rare –use diagnostic vitrectomy if suspected
• Optic Nerve infiltration is anophthalmic emergency, treatment required immediately –treat with systemic + intrathecal chemo. +/-radiation
• Proptosis possible if orbital soft tissue infiltrates.
• May have opportunistic infections secondary to immunocompromise.
• Treatment = low dose radiation, systemic chemotherapy

Medulloepithelioma:

• Meulloepithelioma (diktyoma)
  • Tumor of non-pigmented Ciliary Body epithelium
  • Has benign + malignant forms
  • Congenital
  • Clinical diagnosis usually around age 4-12 years old. Sometimes diagnosed in adults
  • Variably pigmented mass arising from ciliary body (rarely on orinretina)
  • May erode into anterior chamber
  • Treatment
    • Enucleate–DO NOT SURGICALLY RESECT
    • Observe
    • Metastasisis RARE
    • May treat small lesions with brachy therapy (I-125 plaque)

Leiomyomas, Neurilemomas, Neurofibromas:

VERY RARE: Usually misdiagnosed as amelanotic primary uveal melanomaand discovered on histopathology

References:

1. Shields CL, Shields PW, Manalac J, Jumroendararasame C, Shields JA. Review of cystic and solid tumors of the iris. Oman J Ophthalmol, 2013 Sep-Dec; 6(3):159-164.
2. Bianciotto C, Shields CL, Guzman JM, Romanelli-Gobbi M, Mazzuca D Jr, Green WR, Shields JA Assessment of anterior segment tumors with ultrasound biomicroscopy versus anterior segment optical coherence tomography in 200 cases. Ophthalmology. 2011 Jul; 118(7):1297-302.
3. Shields CL, Arepalli S, Lally SE, Lally EB, Shields JA. Iris stromal cyst management with alcohol-induced sclerosis in 16 patients. JAMA Ophthalmol. 2014 Jun;132(6):703-8.
4. Demirci H, Mashayekhi A, Shields CL, Eagle RC, Shields JA. Iris Melanocytoma: clinical features and natural course. Am J Ophthalmol. 2005 Mar; 139(3):468-75.
5. Geisse LH, Robertson DM. Iris Melanoma. Am J Ophthalmol 1985. 99:638-648.
6. Henderson E, Margo C. Iris Melanoma. Archives of Pathology & Laboratory Medicine. 2008 Feb 132(2):268-272.