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Arch Ophthalmol. 2003;121:397-400.

Transpupillary thermotherapy (TTT) is being used increasingly for the treatment of small and some medium-sized choroidal melanomas.^1-3 Although several studies have outlined the complications following TTT, such as tumor recurrence,³ vascular occlusions,⁴ visual field defects,⁵ and retinal detachment,² there are only a few studies dealing with histopathologic findings following TTT.^6-8 In this article, we present clinicopathologic correlations in 10 eyes that required enucleation after TTT in an attempt to improve our understanding regarding potential limitations of TTT.

Methods
We prospectively collected data from all patients with a diagnosis of uveal melanoma who were treated with planned TTT at the Ocular Oncology Service at Wills Eye Hospital (Philadelphia, Pa) between January 1995 and September 2001.³ Only those patients who eventually required enucleation formed the basis of the present study. Institutional review board approval was obtained.

Tumor progression was defined as any increase in tumor thickness or basal diameter detected by ophthalmoscopy, fundus photography, or ultrasonography during the first 3 treatment sessions, without any documented regression. Tumor recurrence was defined as tumor growth after a period of stable regression. All eyes were fixed in neutral buffered formalin and processed routinely for light microscopy. All available histopathologic sections of each globe were reviewed retrospectively by an experienced ophthalmic pathologist. The findings at the site of primary treatment, margins, and away from the primary site were assessed, tabulated, and correlated with clinical findings.

Results
The general information regarding patient demographics and tumor characteristics is presented in Table 1. Among 357 consecutive patients who received TTT as primary treatment of choroidal melanoma, 10 patients (2.8%) eventually required enucleation (Figure 1). Two tumors were clinically amelanotic. Eight tumors touched the optic disc and were classified as juxtapapillary in location. The mean size of the choroidal melanomas was 7.4 mm in basal diameter and 3.1 mm in thickness, requiring an average of 3 sessions of thermotherapy.

View this table: [in this window] [in a new window] Table 1. Tumor Characteristics of 10 Eyes Undergoing Enucleation Following Transpupillary Thermotherapy

View larger version (15K): [in this window] [in a new window] Figure 1. The rate of enucleation following transpupillary thermotherapy as related to the duration of the follow-up period.

Of the total 10 cases requiring enucleation, 8 cases (80%) were related to the failure of the primary tumor to respond, which was either due to tumor progression (3 cases) or to tumor recurrence (5 cases). One case each was enucleated because of persistent rhegmatogenous retinal detachment and neovascular glaucoma (Figure 2). The mean interval between TTT and enucleation was 19.4 months (range, 6-70 months).

View larger version (289K): [in this window] [in a new window] Figure 2. A, A 22-year-old man with juxtapapillary choroidal melanoma in his right eye. B, Following a single session of transpupillary thermotherapy, retinal neovascularization developed, which did not respond to panretinal photocoagulation. Eye was enucleated because of possible tumor recurrence and neovascular glaucoma. C, Pigmented cells buried by thick collagenous postthemotherapy scarring comprise a mixture of melanophages and melanoma cells (hematoxylin-eosin, original magnification x50 [left] and x250 [right]).

The histopathologic findings based on multiple sections from each globe are summarized in Table 2. At the site of thermotherapy application, well-demarcated, full-thickness retinal atrophy and retinal and choroidal fibrosis were observed in all cases (Figure 3). The extent of fibrosis was variable; in 8 cases, fibrosis was minimal, and in 2 cases, it was massive, extending from the level of the retinal pigment epithelium to the underlying choroid. Viable-appearing choroidal melanoma was observed within the areas of TTT application in 5 cases and was noted at the margins of the treatment area in 6 cases. Tumor cells were evident intrasclerally in 3 cases, and 4 cases had extrascleral extension (Figure 3). The tumor was present within the lumina of the intrascleral emissary canals, or had directly infiltrated the scleral lamellae or both.

View this table: [in this window] [in a new window] Table 2. Histopathologic Findings in 10 Eyes Undergoing Enucleation Following Transpupillary Thermotherapy

View larger version (140K): [in this window] [in a new window] Figure 3. A, A 48-year-old woman with a juxtapapillary choroidal melanoma in her left eye. Fundus appearance after a single session of thermotherapy. B, Stable regression following multiple sessions of thermotherapy. C, B-scan ultrasonography suggestive of extraocular extension. D, Melanophages buried by postthermotherapy collagenous scar are seen at higher power in insets. Bleach section discloses bland nuclei and low nuclear-cytoplasmic ratio (main figure: hematoxylin-eosin, original magnification x50; top inset: hematoxylin-eosin, original magnification x100; bottom inset: bleach, original magnification x100). E, Extrascleral nodule of melanoma adheres to the back of the globe, deep to the choroidal aggregate of melanophages seen in part D. Constituent mixture of spindle and epithelioid cells is evident at higher magnification on the right (hematoxylin-eosin, original magnification x10 [left] and x250 [right]).

Comment
The level of hyperthermia during TTT is influenced by many variables such as duration, power, and spot size of the laser beam, and tumor characteristics such as thickness and extent of pigmentation.¹ The potential complications of TTT can be anticipated by effects of hyperthermia on the overlying retina and retinal vessels. The sclera is known to be resistant to hyperthermia.⁹

In all cases in our study, TTT treatment sites were characterized by well-demarcated and abruptly margined areas of retinal atrophy and fibrosis. The underlying sclera seemed normal in cases without extrascleral extension.⁸ In one of our cases, complete atrophy of the overlying retina led to irreparable rhegmatogenous retinal detachment. In 2 cases, there was exuberant retinal fibrosis that obscured the ophthalmoscopic view of the underlying choroidal melanoma that was noted histopathologically. In one case, tumor recurrence was seen only extraocularly without any intraocular component. Although retinal vascular occlusions involving small vessels are fairly common (69%-83% of cases) following TTT, retinal neovascularization is relatively uncommon.⁴ In one of our cases, florid retinal neovascularization led to neovascular glaucoma.

Overall tumor-related complications such as progression and recurrence accounted for the majority of enucleations. Recurrent tumor following TTT can be managed by additional thermotherapy, plaque radiotherapy, or enucleation based on location and extent of the recurrent tumor and the visual potential. The post-TTT enucleation rate of 2.8% in our series compares favorably with the published rates of 2.6% to 7.0%.^{4, 10-11}

In general, the risk of tumor recurrence (about 4% at 1 year and 22% at 3 years) can be minimized by proper case selection and treatment beyond the visible tumor margins.³ The mean time to recurrence is almost 2 years after the initiation of TTT, implying the need for careful long-term follow-up of the patients.³ In our series, 8 cases (80%) were juxtapapillary in location at initial visit—a risk factor identified to predispose to tumor recurrence.³ It is not known whether the risk for recurrence with juxtapapillary tumors is due to difficulty in treating tumors at this location or whether such tumors are inherently more aggressive.

Intrascleral choroidal melanoma was noted histopathologically in 3 cases, and 4 cases developed extrascleral extension. Tumor infiltration of scleral lamellae has been observed in approximately 50% of eyes undergoing primary enucleation.¹² Melanoma cells sheltered in posterior intrascleral emissary canals or scleral lamellae are a potential source of tumor recurrence.⁵ Tumor recurrence may occur intraocularly or extraocularly. Therefore, patients treated with TTT should routinely undergo B-scan ultrasonography to detect extrascleral extension even if they demonstrate satisfactory ophthalmoscopic appearance of regression. Concerns regarding the lack of efficacy of TTT against intrascleral melanoma^{2, 5, 8} have led to a concept of "sandwich therapy."^{2, 11, 13} It is proposed that the combination of TTT and plaque radiotherapy may reduce the risk of tumor recurrence following TTT.¹⁴ Currently, guidelines for use of this sandwich therapy have not been clearly established.

This investigation was supported by the Sarah B. Kant Fund (Dr Singh) from the Eye Tumor Research Foundation, Philadelphia, Pa; the Paul Kayser Award of Merit in Retinal Research (Dr J. A. Shields), Houston, Tex; the Macula Foundation (Dr C. L. Shields), New York, NY; and the Noel T. Simmonds and Sarah L. Simmonds Endowment for Ophthalmic Pathology (Dr Eagle), Wills Eye Hospital, Philadelphia.

Arun D. Singh, MD; Ralph C. Eagle, Jr, MD; Carol L. Shields, MD; Jerry A. Shields, MD
Philadelphia, Pa

Corresponding author: Arun D. Singh, MD, Oncology Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107 (e-mail: arunsingh{at}eyetumors.com).

REFERENCES
1. Journee-de Korver JG, Oosterhuis JA, Kakebeeke-Kemme HM, de Wolff-Rouendaal D. Transpupillary thermotherapy (TTT) by infrared irradiation of choroidal melanoma. Doc Ophthalmol. 1992;82:185-191. FULL TEXT | PUBMED 2. Oosterhuis JA, Journee-de Korver HG, Keunen JE. Transpupillary thermotherapy: results in 50 patients with choroidal melanoma. Arch Ophthalmol. 1998;116:157-162. FREE FULL TEXT 3. Shields CL, Shields JA, Perez N, Singh AD, Cater J. Primary transpupillary thermotherapy for small choroidal melanoma in 256 consecutive cases: outcomes and limitations. Ophthalmology. 2002;109:225-234. FULL TEXT | ISI | PUBMED 4. Currie ZI, Rennie IG, Talbot JF. Retinal vascular changes associated with transpupillary thermotherapy for choroidal melanomas. Retina. 2000;20:620-626. PUBMED 5. Robertson DM, Buettner H, Bennett SR. Transpupillary thermotherapy as primary treatment for small choroidal melanomas. Arch Ophthalmol. 1999;117:1512-1519. FREE FULL TEXT 6. Journee-de Korver JG, Oosterhuis JA, de Wolff-Rouendaal D, Kemme H. Histopathological findings in human choroidal melanomas after transpupillary thermotherapy. Br J Ophthalmol. 1997;81:234-239. FREE FULL TEXT 7. Diaz CE, Capone A Jr, Grossniklaus HE. Clinicopathologic findings in recurrent choroidal melanoma after transpupillary thermotherapy. Ophthalmology. 1998;105:1419-1424. FULL TEXT | ISI | PUBMED 8. Finger PT, Lipka AC, Lipkowitz JL, Jofe M, McCormick SA. Failure of transpupillary thermotherapy (TTT) for choroidal melanoma: two cases with histopathological correlation. Br J Ophthalmol. 2000;84:1075-1076. FREE FULL TEXT 9. Keunen JE, Oosterhuis JA, Rem AI, Journee-de Korver JG. Transscleral thermotherapy in choroidal melanoma: first results. In: Keunen JE, Imhof SI, de Keizer RJW, Moll AC, eds. Proceedings of International Congress of Ocular Oncology. Amsterdam, the Netherlands; 2001:107. 10. Godfrey DG, Waldron RG, Capone A Jr. Transpupillary thermotherapy for small choroidal melanoma. Am J Ophthalmol. 1999;128:88-93. FULL TEXT | PUBMED 11. Seregard S, Landau I. Transpupillary thermotherapy as an adjunct to ruthenium plaque radiotherapy for choroidal melanoma. Acta Ophthalmol Scand. 2001;79:19-22. PUBMED 12. Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study: COMS report No. 6. Am J Ophthalmol. 1998;125:745-766. FULL TEXT | ISI | PUBMED 13. Keunen JE, Journee-de Korver JG, Oosterhuis JA. Transpupillary thermotherapy of choroidal melanoma with or without brachytherapy: a dilemma. Br J Ophthalmol. 1999;83:987-988. FREE FULL TEXT 14. Shields CL, Chao A, Cater J, et al. Combined plaque radiotherapy and transpupillary thermotherapy for choroidal melanoma: tumor control and treatment complications in 270 consecutive patients. Arch Ophthalmol. 2002;120:933-940. FREE FULL TEXT

SECTION EDITOR: W. RICHARD GREEN, MD

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