OCULAR ONCOLOGY FOR THE COMPREHENSIVE OPHTHALMOLOGIST
From the Washington Academy of Eye Physicians and Surgeon’s 2006 Annual Meeting
Devron H. Char, MD, Clinical Professor, Department of Ophthalmology, Stanford University School of Medicine,
and President, Tumori Foundation, Stanford, CA
| UVEAL TUMORS: DIAGNOSIS AND WORK-UP
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| Epidemiology: melanomas of eye rare; usually occur in whites; ≈80% involve choroid (less frequently, ciliary body or
iris); no clear-cut risk factors
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| Masquerade syndromes: if tumor orange-pink, think of hemangioma; if jet black (consider possibility of hemorrhage
or retinal pigment epithelium [RPE] proliferation); if tumor <2 mm thick, cannot make diagnosis of melanoma; extensive
vitreous hemorrhage with lesion <5 mm thick almost never melanoma (unless retinal vessel overlying Bruch’s membrane
and lesion tears through it); multiple melanomas from multiple choroidal tumors extremely rare; ocular pain not seen
with melanoma (absent neovascular glaucoma [NVG]); <1.5% of uveal melanomas occur in young age group; if recent
intraocular surgery, consider possibility of localized choroidal hemorrhage; unilateral media opacity demands diagnostic
ultrasonography (US) every 3 mo due to malignant potential; media opacification after tumor or history of systemic malignancy
raises possibility of tumor; diagnostic US most useful; if patient has possible ocular tumor with pain, weight
loss, and generalized malaise, consider possibility of metastatic tumor
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| Differential diagnosis of uveal melanoma: most common considerations nevi and detachment of choroid or retina;
metastases; hemangioma; rare types of tumors
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| Nevi: drusen on surface; hypopigmented border (sign of chronicity); lipofuscins or orange pigment on surface (more likely
to grow); may be amelanotic; choroidal nevus almost always flat and <6 mm in diameter
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| Choroidal “nevoma”: intermediate pigmented choroidal lesion <10 mm diameter and <3 mm thick; red-orange choroidal
lesion—most likely choroidal hemangioma; black lesions—RPE proliferation or acute hemorrhage; rarely, RPE
proliferations undergo malignant degeneration; RPE adenocarcinomas never metastasize and easily managed
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| Metastases: patients with ocular melanomas otherwise healthy (sick appearance worrisome); in, eg, bronchogenic carcinoma
or renal cell carcinoma, 90% of patients present with eye lesion before discovery of primary neoplasm; US usually
diagnostic; carcinoembryonic antigen (CEA) or cancer antigen (CA)125 studies helpful; metastases amelanotic and do
not form collar buttons; multiple or in both eyes in ≈20% of cases
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| Speaker’s “favorite fake”: mass present only on upgaze (patient had rheumatoid arthritis with area of scleral weakening
from scleritis); scleritis more commonly gives exudative detachment on scan; only 50% of posterior scleritides associated
with pain; caveat (some patients present with scleritis and malignancy)
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| Typical melanoma: globular lesion occasionally breaks through Bruch’s membrane to produce collar button; pattern on
B-scan typical, with acoustical quiet zone; low-to-medium reflectivity on A-scan, with sharp posterior spike (accurate in
≈91% of difficult cases); melanomas do not hemorrhage unless collar-button break hits blood vessel (rare); collar-button
or mushroom-shaped appearance virtually pathognomonic for melanoma (rare in other tumors)
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| Fine needle aspiration biopsy (FNAB): in Cox-model studies, safe and provides important information; easily distinguishes
spindle-cell melanoma from mixed-cell melanoma; comparative genomic hybridization—in melanomas
with poor prognosis, monosomy of chromosome 3 and hyperploid chromosome 8; microwave gene assay—dividing
melanomas into class 1 tumors (no tumor-associated mortality) and class 2 tumors (95% of tumor-related mortality)
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| Conclusion: unilateral media opacity demands diagnostic US; red flags—young patient with mass; painful lesion in absence
of NVG; pink or black lesion; history of systemic malignancy or history of immunologic disorders
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| UVEAL MELANOMA: TREATMENT UPDATE
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| Treatment options (overview): case (small lesion with orange pigment on surface with documented growth; 1.5 mm
from fovea and ≈3 mm from nerve); 810-nm laser (main problem laser-induced hyperthermia); in high-risk nevomas, proton
radiation (charged-particle radiation) would have terrible complications involving visual loss; in some cases, synergy between
laser and proton radiation in trying to keep vision; tendency to use transpupillary thermotherapy (TTT) in thin uveal melanoma
(not tumor >4 mm thick; penetration not sufficient)
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| Complications of laser therapy: major complication failure of local tumor control (rate 25%-70%); laser reasonable
as long as patient watched closely (with prompt intervention, no increase in tumor-related mortality); laser used in tumors
where radiation would cause great visual loss; other potential complications surface contracture and hemorrhage
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| Radiation therapy: tumor localized via indirect ophthalmoscopy and transillumination on cornea; radioactive plaques one
option (speaker prefers proton therapy); radiation destroyed reproductive integrity of tumor by cross-linking of DNA; usually,
first observation loss of subretinal fluid (mean latency ≈6 mo); tumor shrinkage delayed ≈1 yr between treatment and
detection (faster shrinkage associated with poorer survival; tumors cycling quickly more likely to shrink quickly; faster cycling
tumors associated with greater risk for death); good long-term local tumor control in ≈99% of cases with proton radiation
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| Collaborative Ocular Melanoma Study (COMS): in patients with good vision, 5-yr metastatic rate low (in study,
6.4%); concerns about randomization of possible enucleation; larger tumors at greater risk for metastatic disease
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| Particle radiation and NVG: in recent trial, high tumor-control rate, but most eye loss attributable to NVG; by keeping
anterior segment out of entrance beam, incidence of NVG <8%; multiple-beam strategy can avoid anterior segment
and development of NVG
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| Comparative tumor-control rates: speaker more impressed with charged-particle therapy than 125 I brachytherapy
or radioactive plaques; early and late control statistically significantly better with charged particles than brachytherapy;
with particles, failures occur early (if at all); with plaques, failures can occur 20 yr postoperatively (125 I seeds for prostate
brachytherapy have same curve); charged particles more efficacious (in 80% of cases, eye salvaged; better local control
with protons than with plaques); ≈40% of eyes retain good vision
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| Why perform eye wall resections? ocular morbidity of tumors >8 mm thick increased 10-fold, compared to those <6
mm thick; complication rate high with irradiation of very large uveal melanomas (mean thickness 8-8.5 mm); morbidity
rates lower with eye wall resection; most surgeons now use adjunctive lower-dose radiation; problem of reproducibility
of visual function with resection; study of large tumors—≈13 mm diameter and slightly >8 mm thickness; >80% of
eyes retained; ≈55% had final vision 20/40; better outcomes than with radiation alone; contraindications—average age
of melanoma patient 60 yr (many hypertensive); tumors >15 mm difficult to treat surgically; if break through Bruch’s
membrane, procedure does not work well; posterior choroidal tumors <5 mm thick or >15 mm in diameter do better with
radiation; thick lesions not >15 mm diameter do better with added resection than with radiation alone
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| Enucleation: indications—patient request; large tumor (>40% of ocular volume) already associated with significant
neovascularization; failure of alternative therapy (rare); contraindications—diagnostic uncertainty; absence of metastatic
disease (eye not removed unless painful); eye with good vision potential
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| Metastasis: unlike cutaneous melanomas, metastatic uveal melanomas mainly migrate to liver; most metastases occur
within 3 yr, but some have latency of 48 yr; adjuvant therapies not effective; first sign of metastasis in uveal melanoma
(paper by Char and Hogan)—liver involved in ≈60%; subcutaneous nodules ≈25%; positron emission tomography
(PET) and computed tomography (CT) most effective strategies for detecting metastatic disease; if disease cannot be
treated effectively, serum γ-glutamyltransferase (GGT), lactic dehydrogenase (LDH), and physical examination
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| ORBITAL TUMORS: DIAGNOSIS AND MANAGEMENT
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| Examination techniques: if patient has proptosis and arteriovenous (AV) malformation or varix, Valsalva maneuver
helpful in making diagnosis; physical findings aid differential diagnosis; eye displaced outwardly (axial proptosis; suggests
intraconal tumor, optic nerve tumor, or thyroid disease); eye down and toward nose (lacrimal fossa mass); eye displaced
down (superior orbital or central nervous system [CNS] lesion); commercially available exophthalmometers have
±2-mm variability in expert hands; eyelid changes—bilateral lid retraction and proptosis (thyroid disease); ptosis with
inflammation helpful for inflammatory process; S-shaped lid (lacrimal fossa lesion); erythematous eyelid (systemic immune
disease or idiopathic pseudotumor); conjunctival changes—generally not very helpful; diffuse scleritis contrasts
with signs of thyroid disease (typically, enlarged vessels just over insertions of muscles; rest of sclera normal)
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| Differential diagnosis of proptosis: thyroid disease by far most common etiology in adults; next, idiopathic inflammatory
processes (≈20%); then tumors or trauma, infectious simulations, and other conditions involving sinus or brain
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 | For systemic illness: proptosis with previous history of lymphoma or malignancy; immunologic disease; 40% of people
with bilateral orbital disease have underlying systemic process; systemic symptoms—weight loss; fatigue; malaise;
lymphadenopathy; bone invasion on imaging suggests systemic lesion
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| For malignancy in patients with proptosis: unilateral lacrimal fossa lesion and perineural pain is adenoid cystic carcinoma;
bone invasion on imaging; if patient looks sick, consider possibility of immunologic disease (eg, systemic lupus
erythematosus [SLE]); palmar rash and lacrimal gland lesions (syphilis, lymphomas); involvement in adjacent structures
or rapid growth raises suspicion of malignant process
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| When is magnetic resonance imaging (MRI) better than CT? advantages of MRI—MRI crucial in adult
with vision loss; compressive optic neuropathy, optic nerve sheath meningioma, or sphenoid wing meningioma causing
vision loss can be missed on CT and seen on MRI; in children with orbital tumors, MRI pattern pathognomonic in differentiating
hemangioma from rhabdomyosarcoma; apart from those exceptions, CT cost-effective and reasonable; advantages
of CT—new helical or spiral CTs can image whole orbit in <1 min; in very young children, anesthesia
unnecessary; CT probably best choice if patient has trauma; patients with pacemaker, who are claustrophobic, or who
have magnetic material implanted cannot use MRI; bone invasion better delineated on CT
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| Differential diagnosis by area of involvement: extraocular muscles—thyroid orbitopathy most common; idiopathic
myositis; metastases; thyroid—typically involves inferior rectus; medial rectus less common; lateral or superior
rectus; finally, obliques; typically, causes swelling of muscle with sparing of tendon; hemangiopericytoma involving
medial rectus—correct diagnosis impossible without histologic or cytopathologic confirmation; lacrimal fossa
lesions—treacherous; malignant lesions unilateral (if bilateral, could be systemic problem, but not malignant epithelial
lesion); bone involvement with adenoid cystic carcinoma common (not common in benign lesions); pseudoinvasion occasionally
seen in unifocal histiocytosis; inflammatory signs suggest idiopathic inflammation or lymphoma; perineural
pain with unilateral lacrimal fossa glandular lesion (suspect adenoid cystic lesion)
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| Work-up and differential diagnosis: sarcoidosis common (if patient not on steroids, serum angiotensin-converting
enzyme with limited gallium scan 97% sensitive); tuberculosis (especially in immigrant population); lacrimal gland lesion
with palmar rash suggests syphilis; leprosy; mumps in young children and mononucleosis in teenagers can cause bilateral
or unilateral lesions
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| Management of unilateral lesion: MRI shows only whether bone involved; large lacrimal gland lesion (assume epithelial
lesion until proven otherwise); biopsy not indicated (if benign mixed tumor and not excised completely, problem
will recur; ≈20% undergo malignant degeneration); work up unilateral lesion for sarcoidosis and other conditions
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| Evaluation of intraconal lesions: depends on age; in young children, mainly lesions of optic nerve; Valsalva maneuver
(can have AV malformations or varices); rule out systemic disease; encapsulated round lesion (benign mesenchymal
tumor; cavernous hemangioma [most common], neurofibromas, or neurilemomas); diffuse (think of inflammatory lesion;
sometimes metastases or lymphomas); optic nerve lesion (depending on age of child, think of glioma; in older person,
lymphoma or optic nerve sheath meningioma); extraconal lesions that involve bone—in very young children, think of
metastasis or neuroblastoma; in slightly older person, think of eosinophilic granuloma; in elderly, metastasis; location,
systemic symptoms, and imaging pattern helpful
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| Changes in orbital management: evaluation of lymphoid tumor now aided by FNAB (permits flow cytometry); other
options standard immunostaining and Southern blot; microscope-mounted CO2 laser—useful in debulking lesions and
for very vascular tumors; many tumors considered “horrible” in past now easily treated; newer guidance systems for CT
or MRI—accurate; very helpful preoperatively; newer radiation delivery—in recent study, 90% of children treated for
orbital rhabdomyosarcoma had severe ophthalmic complications at 10 yr; new approaches marry computer to radiation to
focus radiation and avoid vital structures; intensity-modulated conformal therapy most useful (Cyberknife and proton beams
also helpful); with these approaches, speaker predicts that complication rate in rhabdomyosarcoma will decrease from 90%
to 25%; avoidance of optic nerve decreases complications dramatically
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Educational Objectives
| The goal of this program is to educate the listener about ocular tumors. After hearing and assimilating this program, the clinician
will be better able to:
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| 1. Identify uveal tumors.
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| 2. Describe the differential diagnosis of uveal tumors.
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| 3. Recognize uveal melanoma.
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| 4. Choose appropriate therapy for uveal melanoma.
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| 5. Diagnose and manage orbital tumors.
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Suggested Reading
Berger M, Char DH: Interactive image guidance for surgical localization of orbital apical tumors. Orbit 21:199, 2002;
Bove R, Char DH: Nondiagnosed uveal melanomas. Ophthalmology 111:554, 2004; Char DH et al: Analysis of
melanoma cell type in uveal melanoma following treatment failure. Am J Ophthalmol 138:543, 2004; Char DH et al:
Eye-wall resection. Trans Am Ophthalmol Soc 98:153, 2000; Char DH et al: Intraocular biopsy. Ophthalmol Clin
North Am 18:177, 2005; Char DH et al: Iris ring melanoma. Br J Ophthalmol 90:420, 2006; Char DH et al: Laser
and proton radiation to reduce uveal melanoma-associated exudative retinal detachments. Trans Am Ophthalmol Soc
101:53, 2003; Char DH et al: Laser and proton radiation to reduce uveal melanoma-associated exudative retinal detachments.
Am J Ophthalmol 136:180, 2003; Char DH et al: Proton teletherapy of uveal melanoma. Int Ophthalmol Clin
46:41, 2006; Char DH et al: Uveal tumor resection. Br J Ophthalmol 85:1213, 2001; Char DH, Phillips TL: Controversy
regarding pre-enucleation radiation for uveal melanoma. Arch Ophthalmol 121:1346, 2003; Char DH: Ocular
melanoma. Surg Clin North Am 83:253, 2003.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Dr. Char was recorded at the Washington Academy of Eye Physicians and Surgeons Annual Meeting 2006, presented
March 30-31, 2006, in Seattle, WA. The Audio-Digest Foundation thanks Dr. Char and the Academy for their cooperation
in the production of this program.
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