Steven H. Lin and Vincent J. Lee
How does intraocular melanoma rank in terms of incidence among the various eye malignancies?
Intraocular melanoma is #1 among primary cancers (#1 overall is ocular mets).
What is the incidence of ocular melanoma in the U.S.? Is there a race predilection?
1. 4 in 1 million (~1,500 to 2,000 cases/yr of ocular melanoma)
2. Yes. 98% of pts are white.
What is the most common site in the eye where ocular melanomas arise?
Uvea, mostly choroidal (85%) > adnexa (10%) > conjunctiva (5%)
What is the cell of origin for ocular melanoma?
Ocular melanoma arises from uveal melanocytes of the uveal stroma (neural crest origin).
What are the components of the uveal tract?
The choroid, cilary body, and iris comprise the uveal tract.
Name the layers of the choroid from outer to inner.
Layers of the choroid (outer to inner):
1. Haller layer
2. Sattler layer
4. Bruch membrane
What are the basic layers of the globe?
Outer fibrous layer (sclera), middle vascular layer (choroid), and inner nerve layer (retina)
What is the name for the ant termination of the retina?
The ora serrata is the ant termination of the retina.
What region in the retina is particularly important for color vision?
The macula is important for color vision.
Where is the optic disc relative to the macula?
The optic disc is 2 mm medial to the macula (~1.5 mm in diameter).
What are some of the risk factors for developing ocular melanoma?
UV exposure, white, family Hx of ocular melanoma, and personal Hx of cutaneous melanoma
What is the most common chromosomal abnormality seen in ocular melanoma?
Loss of chromosome 3 and amplification of 8q (50%)
What are the histologic subtypes of ocular melanoma, and which carry the best and worst prognosis?
Spindle cell (best), epithelioid (worst), and mixed (if <50% epithelioid histology)
What % of pts with ocular melanoma present with DM at Dx? What is the most common location?
1%–2% present with DM. The liver is the most common site (5%–20% DM rate over 5 yrs).
What are the different ways melanoma can spread within the globe?
Melanoma can spread intraocularly (through the vitreous, aqueous, or along ciliary vessels/nerves); extraocularly (through the optic nerve, transsclerally, vascular tracking), and through extrascleral extension (10%–15%)
What tumor characteristics predict for DM in ocular melanoma? What is the 5-yr mortality rate in these pts?
Epithelioid histology, large tumors, ant location (ciliary body invasion), monosomy 3, scleral penetration, ↑ mitotic rate, ↑ Ki-67, pleomorphic nucleoli, optic nerve invasion, ↑ MIB-1 index, vascular networks of closed vascular loops, extraocular extension
The 5-yr mortality rate is 55%.
What is the long-term (>10-yr) DM rate from ocular melanoma?
50% of ocular melanoma pts develop DMs at 15 yrs.
How do pts with ocular melanoma normally present?
Most (one third) pts are asymptomatic. Ocular melanoma is usually found on routine exam; otherwise, pts detect it themselves due to vision loss, scotoma, flashing lights, or pain (rare).
What is the workup for a pt with suspected ocular melanoma?
Suspected ocular melanoma workup: H&P, CBC (LFTs), ophthalmic/funduscopic/slitlamp exam, visual acuity/visual field testing, US (Kretz A-scan, immersion B-scan), fluorescein angiography, MRI, PET/CT to r/o mets
Is Bx commonly done for ocular melanoma?
No. With Bx, there is a potential for tumor seeding. The Dx is made by exam and imaging.
What are simulation lesions?
Simulation lesions are lesions that may look like melanoma, such as nevi, hemangiomas, retinal detachment, age-related disciform lesions, and mets.
What feature does ocular melanoma manifest on standard A-scan US?
An acoustic “quiet” zone (central hypoechoic area) vs. mets or hemangiomas (have higher internal reflectivity)
What features do ocular melanomas exhibit on fluorescein angiography?
On fluorescein angiography, ocular melanomas exhibit a double circulation pattern and fluorescein leakage (appearing as hot spots).
What is the T staging of choroidal/ciliary body melanoma based on the latest AJCC (2009) staging guidelines?
AJCC staging is based on 4 tumor size categories that depend on tumor diameter and height as follows (Fig. 24.1):
1. T1: tumor size category 1
2. T2: tumor size category 2
3. T3: tumor size category 3
4. T4: tumor size category 4
For the T staging of choroidal/ciliary body melanomas, what do the designations a–e represent?
1. a: no ciliary body involvement/extraocular extension
2. b: +ciliary body involvement
3. c: no ciliary body/+extraocular extension ≤5 mm
4. d: +ciliary body/+extraocular extension ≤5 mm
5. e: +extraocular extension ≥5 mm
Describe the AJCC 7th edition 2009 TNM staging for choroidal/ciliary body melanomas.
1. Stage I: T1aN0M0
2. Stage IIA: T1b-dN0M0 or T2aN0M0
3. Stage IIB: T2bN0M0 or T3aN0M0
4. Stage IIIA: T2c-d, T3b-c, T4aN0M0
5. Stage IIIB: T3d, T4b-cN0M0
6. Stage IIIC: T4d-eN0M0
7. Stage IV: any TN1M0, any T, any NM1a-c
For the M staging of choroidal/ciliary body melanomas, what do the designations a–c represent?
1. Ma: largest diameter of met ≤3 cm
2. Mb: largest diameter of met 3.1–8 cm
3. Mc: largest diameter of met ≥8 cm
In the Collaborative Ocular Melanoma Study (COMS) staging system, what are COMS small, medium, and large lesions?
COMS staging is based on apical height (AH) and basal diameter (BD):
1. Small: AH 1–2.5 mm, BD ≤5–16 mm
2. Medium: AH 2.6–10 mm, BD 6–16 mm
3. Large: AH ≥10 mm, BD ≥16 mm
What are the 10-yr OS rates of COMS small, medium, and large tumors? Pts with DM?
10-yr OS for COMS tumors:
1. Small: 80%
2. Medium: 60%
3. Large: 30%–40%
4. DM pts: <7 mos
What is the melanoma-related mortality for COMS small lesions after 8 yrs?
Mortality is 4% for COMS small lesions after 8 yrs.
In order of importance, what are the 3 main goals of Tx in the management of ocular melanoma?
Main goals of ocular melanoma Tx (in order of importance):
1. Preserve life
2. Preserve eye
3. Preserve vision
What is the preferred management approach for COMS category small uveal melanomas?
Observation or local therapy (transpupillary thermotherapy, photocoagulation, PDT, local resection, or enucleation [pt choice])
When is RT employed in the management of COMS category small uveal melanomas?
RT is employed when there is progression after conservative management (i.e., observation or other local Tx).
What are the eligibility criteria for observing uveal melanomas?
COMS small, inactive lesions, and good baseline visual function
When should Tx for uveal melanomas be initiated after observation?
Tx for uveal melanomas should be initiated when growth is detected or there are pigmentation changes.
If resection is employed for small melanomas, for what ocular location is it generally reserved?
Resection is reserved for lesions of the iris or ciliary body. It is not used for uveal lesions because of the visual impact.
In the COMS trials, pts with small uveal melanomas were observed with close follow-up. What % of pts progressed after 5 yrs?
~33% of pts with small melanomas progressed (63% of the tumors did not grow).
What features of small uveal melanomas were found to be associated with growth after observation?
Orange pigmentation (6.4 times), no drusen and no adjacent retinal pigmentary changes (4.2 times), >2 mm thickness (4.4 times), >12-mm BD (5.2 times)
What are the Tx options for COMS medium melanomas?
Enucleation, plaque brachytherapy, and proton RT
When is enucleation a preferred approach for the management of uveal melanoma?
Pt choice, as salvage therapy, tumor involving >40% of intraocular volume, tumor in a nonfunctional eye, symptomatic pt (pain), eye with marked neovascularization, and extrascleral extension
What are the indications for the use of plaque brachytherapy?
Plaque brachytherapy is used for organ preservation for COMS medium lesions and small progressive tumors after observation.
What are the max AH and BD sizes allowed for plaque brachytherapy?
For plaque brachytherapy, max allowed sizes are ≤ 10-mm (3–8 mm optimal) AH and 16-mm BD.
Under what circumstances should notched plaques be used?
Notched plaques are typically used for peripapillary tumors.
What is the most common isotope used in plaque brachytherapy? What is the dose rate?
I-125, at a dose rate of 0.7–1 Gy/hr (Tx times vary from 4–7 days)
How is the dose prescribed with plaque brachytherapy?
85 Gy to the tumor apex (or 5 mm from the internal surface of the sclera if the height is <5 mm), with a 2-mm margin around the tumor (or a plaque size equal to 4 mm + greatest BD)
When is proton beam the preferred RT modality in the Tx of uveal melanoma?
Proton beam is used not only as a substitute for plaque brachytherapy or enucleation but also for large tumors, tumors near the optic nerve, tumors near the macula, or tumors under the orbital muscles.
How is proton beam RT prescribed in the Tx of uveal melanoma?
50–70 cobalt Gray equivalents (CGE) in 5 fx over 7–10 days (though 50 CGE produces equivalent LC with less visual loss in RCT comparing 50 with 70 CGE (Gragoudas ES et al., Arch Ophthalmol 2002)
What is the long-term LC rate of proton beam compared to plaque brachytherapy?
1. Proton beam: 95%
2. Plaque brachytherapy: 82%–94%
What is the 5-yr DM rate of ocular melanoma after Tx with either protons or brachytherapy?
The 5-yr DM rate after local RT is ~16%–20%.
What is the randomized phase III study that compared the efficacy of enucleation vs. plaque brachytherapy for medium-sized uveal melanomas?
COMS study (Report No. 28, Arch Ophthalmol, 2006): 1,317 pts. There was no difference in all-cause mortality and melanoma-specific mortality. 12-yr OS was 17%–21%.
In the COMS medium trial, what is the 5-yr secondary enucleation rate after plaque brachytherapy? To what is it due?
The 5-yr secondary enucleation rate is 13% due to Tx failure or ocular pain from brachytherapy complications.
What is the standard management for large uveal melanomas?
Enucleation. Charged particles (protons) can also be used.
What % of pts present with large uveal melanomas?
30% of pts present with large uveal melanomas.
Per the COMS trial, does preop EBRT improve outcomes over enucleation alone for COMS large tumors?
No. In the COMS trial, there was no OS or DFS difference between the 2 groups.
What are some early and late complications associated with plaque brachytherapy?
1. Early: pain, bleeding, diplopia, infection, edema
2. Late: retinopathy (42% at 5 yrs, increasing to 80%–90% thereafter), cataracts, keratitis, optic neuropathy
The use of what agent has recently been associated with a lower incidence of macular edema after plaque brachytherapy?
Triamcinolone (periocular injections). In an RCT, macular edema rates were 58% in the control group vs. 36% in the triamcinolone arm (SS). (Horgan N, Ophthalmology 2009)
What % of pts have loss of ≥6 lines of vision 3 yrs after plaque brachytherapy?
~50% of pts have significant vision loss after plaque brachytherapy.
What % of pts have cataracts 5 yrs after plaque brachytherapy?
83% of pts develop cataracts after plaque brachytherapy.
How should pts treated with plaque brachytherapy be followed?
Plaque brachytherapy follow-up: H&P, ocular US q3mos × 1 yr, q4mos in 2nd yr, q6mos in 3rd and 4th yrs, then annually; CT C/A/P or liver US q6mos with LFTs (can detect >95% of mets)
Are periodic LFTs alone adequate to r/o liver mets?
No. There is very poor sensitivity (15%), PPV (46%), and NPV (71%), with a specificity of 92%. Adding liver US to LFTs increases the detection rate to 95%. (Eskelin S et al., Cancer 1999)
What is the best way to detect liver mets? What is the main disadvantage of this modality?
PET/CT is the best imaging modality for the detection of liver mets. The cost and availability of such testing is the main disadvantage.
FIGURE 24.1 Primary ciliary body and choroidal melanomas are classified according to the 4 tumor size categories shown. (Edge SD, Byrd DR, Compton CC, et al., eds. AJCC cancer staging manual. 7th ed. New York: Springer; 2009, p 549.)