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Cryotherapy as a Primary Treatment for Choroidal Melanoma
Arch Ophthalmol. 2002;120:400-403.
The treatment of small melanocytic tumors of the uvea is appealing because
of the prospect of local destruction of a potentially lethal tumor while it
is still confined to the eye. However, enthusiasm for treating small melanocytic
tumors of the uvea has been tempered by the lack of an effective local treatment
that is free from significant local side effects and by the difficulty in
identifying which small uveal melanocytic lesions should be treated. In the
past few years, several studies have helped identify which small uveal melanocytic
tumors are at particularly high risk for growth and/or metastasis.1-2 Identification of high-risk small
tumors has prompted reevaluation of the management of these tumors and promoted
the development of vision-sparing treatment modalities.
Cryotherapy has been used in a limited fashion for the treatment of
uveal melanomas.3-4 Lincoff
et al3 and Brovkina et al4
evaluated cryotherapy in small series of patients with uveal melanoma. In
both series the effectiveness of cryotherapy was limited by exudative retinal
detachment and incomplete tumor destruction. However, in both of these trials,
medium to large melanomas were treated, and the treatment was designed to
destroy the tumor in 1 treatment session. Herein we report a prospective trial
of cryotherapy in the treatment of 5 patients with small, growing choroidal
melanocytic tumors with the use of multiple treatment sessions to limit the
complications of the procedure and to ultimately achieve a flat chorioretinal
scar.
Patients, Materials, and Methods
Patients were considered eligible for this trial if (1) they had photographically
documented growth of a choroidal lesion with the ophthalmoscopic and echographic
features of a choroidal melanoma (photographically documented growth was defined
as an increase in the size of the tumor, relative to retinal landmarks, as
determined by comparison of serial color photographs); (2) the thickness of
the choroidal tumor measured less than 3.0 mm; and (3) the basal diameter
was less than 16 mm. Tumors that extended into the ciliary body were not included
in this trial, but peripapillary tumors were eligible. This decision was based
on the lack of vision-sparing options for patients with peripapillary choroidal
melanomas. No specific minimum diameter or thickness was required as long
as the tumor met the above requirement for documented growth. Patients were
not included in the trial if they had undergone prior treatment for choroidal
melanoma, including irradiation, laser, or surgery. All patients underwent
pretreatment and posttreatment examination, color fundus photography, and
A- and B-scan echography. Patients were examined at a minimum of 1 day prior
to treatment, at the time of treatment, 1 day posttreatment, 7 to 14 days
posttreatment, 3 months posttreatment, and then at 6-month intervals. Other
visits were permitted at the discretion of the treating ophthalmologist. Visual
acuities were recorded using a projected visual acuity system but were not
standardized.
The tumors were treated with a double freeze-thaw method that uses a
conventional retinal cryoprobe. The end point of each freeze was whitening
of the surface of the tumor. Applications with the cryoprobe were placed in
an overlapping fashion so that the entire tumor was treated. One patient (patient
3) with a peripapillary tumor was treated with an endocryoprobe to try to
limit the damage to the optic nerve. Patients were re-treated at 4- to 6-week
intervals until a flat chorioretinal lesion, as determined by ophthalmoscopy
and echography, was present. The protocol was approved by the Oregon Health
Sciences University Institutional Review Board for enrollment of 8 patients.
Five patients were enrolled in the trial between 1989 and 1999, at which point
recruitment was closed.
Results
The pretreatment and postreatment clinical features of the tumors are
summarized in Table 1. Pretreatment
and postreatment fundus photographs are shown in Figure 1. Treatment of all the tumors resulted in the desired clinical
end point of a flat chorioretinal scar. This appearance was maintained throughout
the follow-up period. The number of treatments required to achieve this end
point varied from 2 to 5. In patients 4 and 5 there is a small central area
of increased pigmentation (Figure 1
H-J), but these areas are completely flat and have not shown an increase in
size over the follow-up period.
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Color fundus photographs of patients 1 (A and B), 2 (C and D), 3
(E and F), 4 (G and H), and 5 (I and J) before and after cryotherapy, respectively.
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Notable complications of the treatment included a visual acuity of no
light perception in 1 patient (patient 1). This patient had a peripapillary
tumor, and optic nerve damage resulted from direct cryo-injury to the optic
nerve at the time of treatment. Loss of vision occurred immediately following
cryotherapy and there was no recovery of vision following the injury. Patient
2 has age-related macular degeneration and developed a subfoveal neovascular
membrane that is thought to be unrelated to the cryotherapy. Patient 3 developed
a branch retinal vein occlusion that did not significantly affect her vision.
Patient 5 developed a transient exudative retinal detachment and an epiretinal
membrane with a reduction in visual acuity from 20/20 to 20/30.
Patient 1 died from renal and cardiovascular disease 125 months after
treatment of his intraocular tumor. There was no clinical evidence of metastatic
disease. An autopsy was not performed. Patients 2 through 5 are alive without
clinical evidence of metastatic disease. The mean follow-up in the 5 patients
is 65 months, with a range of 16 to 125 months.
Comment
Treatment of small, growing melanocytic tumors remains a controversial
topic. Risk factors for growth of small melanocytic tumors have been reported
in 2 studies. Shields et al1 found that
greater initial tumor thickness, posterior margin of the tumor touching the
optic nerve, symptoms of flashes and floaters, orange pigment on the surface
of the tumor, and subretinal fluid predicted growth. The Collaborative Ocular
Melanoma Study group found that factors predictive of the growth of small
melanomas were a greater initial diameter or thickness, presence of orange
pigment on the surface of the tumor, the absence of drusen, and the absence
of retinal pigment epithelium changes at the margin of the tumor.2 Risk factors for metastasis of small choroidal
melanomas have been reported as posterior margin of the tumor touching the
optic nervehead, documented growth, and greater initial tumor thickness.1 Only small, growing melanomas were treated in this
trial.
Cryotherapy has received little attention as a means of destroying uveal
melanomas. Theoretically, this method has several potential advantages: (1)
melanin-containing cells are sensitive to destruction by freezing; (2) cryotherapy
is an accepted method of treating melanomas elsewhere, including the conjunctiva;
(3) cryotherapy has been used for more than 20 years in treating retinal diseases,
including vascular tumors, retinoblastoma, retinal tears, and retinal detachment;
(4) when using cryotherapy, the approach is from the choroid; thus, in addition
to a direct effect on the tumor cells, cryotherapy can have an additional
effect of compromising the tumor's blood supply; and (5) transscleral treatment
also results in treatment of intrascleral tumor cells.
The acute effects of cryotherapy on uveal melanomas has been studied
by Hidayat et al.5 These authors found that
following rapid freezing there were ultrastructural changes that included
plasmalemmal breaks, dissolution of cytoplasmic matrix, and damage to cellular
organelles all of which suggest a lethal effect on melanoma cells. These authors
also studied one melanoma that was treated with rapid freezing 6 months prior
to enucleation. The tumor was incompletely treated, but in the area of cryotherapy,
there was extensive necrosis of tumor cells and infiltration with melanophages.
A substantial number of complications occurred in our small patient
population. External cryotherapy to a peripapillary tumor resulted in a visual
acuity of no light perception due to cryoinjury to the optic nerve. This complication
was later avoided by using an endocryoprobe to successfully treat a second
peripapillary tumor. Less severe complications included branch retinal vein
occlusion, transient exudative retinal detachment, and epiretinal membrane
formation. Despite these complications, 4 of the 5 patients maintained good
visual acuity after cryodestruction of the tumor (1 subsequently lost vision
in the treated eye owing to age-related macular degeneration).
Other options for treating small, growing melanomas include radiation
therapy or transpupillary thermotherapy (TTT). Radiation therapy of small
tumors carries with it a high likelihood of loss of central vision if the
optic nerve or fovea receives a radiation dosage in excess of 3000 to 4000
rads equivalents.
What role cryotherapy and TTT will have in the treatment of small choroidal
melanomas is not known. Both treatments require multiple treatment sessions
to limit complications. Transpupillary thermotherapy has the advantage of
not requiring conjunctival incisions and having a more discrete border between
treated and untreated areas. Cryotherapy has the advantage of a visual end
point to each treatment session. Unlike TTT, cryotherapy is a transscleral
treatment and should result in treatment of the intrascleral tumor in the
area of cryotherapy. Certain tumor characteristics may be a relative indication
for one type of treatment, eg, tumor pigmentation and location. More peripheral
tumors may be easier to treat with cryotherapy while posterior tumors may
be easier to treat with TTT. Transpupillary thermotherapy appears at this
time to be more effective in more pigmented tumors, so lack of pigmentation
may be a relative indication for cryotherapy. Finally, the 2 treatments are
not mutually exclusive and may find utility in combination with each other,
or with irradiation. Both treatments could find utility in the treatment of
marginal recurrences of initially irradiated tumors. Whether either TTT or
cryotherapy will result in permanent tumor eradication requires further follow-up
of treated patients. The mean follow-up in this trial was 65 months, but given
the small size of the tumors and the slow growth of uveal melanomas, additional
time is necessary to be certain late recurrences will not develop.
In conclusion, we have used cryotherapy to treat 5 patients with small,
growing melanocytic tumors. All tumors were treated to an end point of a flat
chorioretinal scar and maintained this end point over the follow-up period.
Using multiple treatment sessions, we were able to avoid the incomplete tumor
destruction and intraocular morbidity reported in earlier trials about the
cryodestruction of choroidal melanomas.
AUTHOR INFORMATION
This study was supported in part by an unrestricted grant from Research
to Prevent Blindness, New York, NY.
David J. Wilson, MD;
Michael L. Klein, MD
Portland, Ore
Corresponding author: David J. Wilson, MD, Casey Eye Institute, Oregon
Health Sciences University, 3375 SW Terwilliger Blvd, Portland, OR 97201 (e-mail: wilsonda{at}ohsu.edu).
REFERENCES
1. Shields CL, Shields JA, Kiratli H, De Potter P, Cater JR. Risk factors for growth and metastasis of small choroidal melanocytic
lesions. Ophthalmology. 1995;102:1351-1361.
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2. Collaborative Ocular Melanoma Study Group. Factors predictive of growth and treatment of small choroidal melanoma:
COMS Report No. 5. Arch Ophthalmol. 1997;115:1537-1544.
ABSTRACT
3. Lincoff H, McLean J, Long R. The cryosurgical treatment of intraocular tumors. Am J Ophthalmol. 1967;63:389-399.
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4. Brovkina AF, Ziangirova GG, Kornarov BA. Cryodestruction of choroidal melanomas. Vestn Oftalmol. 1977;2:61-63.
5. Hidayat AA, LaPiana FG, Kramer KK, Whitmore PV, Wertz FD, Rao NA. The effect of rapid freezing on uveal melanomas. Am J Ophthalmol. 1987;103:66-80.
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SECTION EDITOR: W. RICHARD GREEN, MD
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
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