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Clinicopathologic findings inchoroidal melanomas after failedtranspupillary thermotherapy
Clinicopathologic Findings in Choroidal Melanomas After Failed Transpupillary Thermotherapy RENZO A. ZALDIVAR, MD, THOMAS M. AABERG, JR., MD, PAUL STERNBERG, JR., MD, RHONDA WALDRON, MMSC, AND HANS E. GROSSNIKLAUS, MD
● PURPOSE: To review the clinicopathologic features of eyes enucleated after failed transpupillary thermotherapy. ● DESIGN: Retrospective review. ● METHODS: Pathology reports in the L.F. Montgomery Laboratory between 1998 and 2002 were searched for enucleated eyes with choroidal melanoma that had been treated only by transpupillary thermotherapy (TTT) prior to enucleation. The clinical features of the patients, including ultrasonography examination, were reviewed and compared with the pathologic findings. ● RESULTS: Seven eyes from seven patients had been enucleated, representing 8% of eyes treated with TTT at our institute during the period studied. The primary indication for enucleation was tumor growth. The melanomas tended to grow laterally, with minimal if any increase in thickness. Five of the seven eyes histologically demonstrated extrascleral extension, which was detected by ultrasonography prior to enucleation in only one of those eyes. ● CONCLUSIONS: Choroidal melanoma may continue to grow along a path of least resistance after TTT. The melanoma may extend laterally in the choroid and through emissary canals. Early extrascleral extension may be difficult to detect by ultrasonography. (Am J Ophthalmol 2003;135:657– 663. © 2003 by Elsevier Inc. All rights reserved.)
U
VEAL MELANOMA IS THE MOST COMMON PRIMARY
intraocular malignancy with an annual incidence of 6 to 8 per million population.1,2 The choroid is the most common part of the uveal tract that gives rise to melanoma. Over the past several decades, numerous eye-
Accepted for publication Nov 25, 2002. From the Department of Ophthalmology (R.A.Z., P.S., R.W., H.E.G.), Emory University, Atlanta, Georgia and Associated Retinal Consultants (T.M.A.), Grand Rapids, Michigan. Supported in part by an unrestricted department grant from Research to Prevent Blindness, Inc, New York, New York. Inquiries to Hans E. Grossniklaus MD, L.F. Montgomery Ophthalmic Pathology Laboratory, BT 428 Emory Eye Center, 1365 Clifton Rd, Atlanta, GA 30322; e-mail: [email protected] 0002-9394/03/$30.00 doi:10.1016/S0002-9394(02)02171-2
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2003 BY
salvaging therapies for uveal melanoma have been developed. Conservative treatment modalities have included radioactive plaque, local resection, and various heatproducing methods.3– 8 Radioactive plaque therapy has been shown to stabilize or reduce melanoma size in more than 90% of cases, although 40% of plaqued eyes develop radiation complications.9,10 Transscleral resection of choroidal melanoma has been performed for more than a decade, although complication rates are greater than 20%.3,11 Heat-inducing methods include photocoagulation (⬎65 C), hyperthermia (44 C), and thermotherapy (45 to 65 C).3 Heat-inducing methods, either alone or in combination with other treatments, have recently received much attention. Transpupillary thermotherapy (TTT) has shown evidence of clinically decreasing tumor size with few complications.3,12–16 Transpupillary thermotherapy uses infrared light produced by a diode laser (810 nm) to induce tissue hyperthermia (45 C to 65 C). The laser is focused through the dilated pupil onto the tumor with the spot size ranging from 2 to 3 mm and an exposure time of 1 minute. At this temperature and with exposure time, tumor size has been shown to progressively decrease, even after only one treatment.16 The early histopathologic effects of experimental TTT have been described.17,18 Two studies examined the histopathologic effects after failed TTT in four eyes.19,20 In this study, we report the histopathologic features in seven eyes of seven patients who underwent enucleation after failed TTT. We correlated the pathologic findings with preoperative clinical findings, including the ultrasound appearance of the melanomas.
METHODS THE INSTITUTIONAL REVIEW BOARD OF EMORY UNIVERSITY
approved the study, including a retrospective chart review and correlation with histopathologic findings. A review of the diagnoses in the L.F. Montgomery Ophthalmic Pathol-
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those patients. There was histologic evidence of intrascleral extension in all four patients. Only one patient had B-scan ultrasonographic evidence of extrascleral extension before enucleation (patient 2). In addition to that case, four additional eyes were histologically found to exhibit extrascleral extension of the melanoma (patients 1, 5, 6, and 7). Tumor growth in basal diameter occurred in three patients, and one patient exhibited growth in both basal diameter and height. The percent increase in basal diameter exceeded the percent increase in height in this patient. Two patients exhibited a decrease in tumor basal diameter and height. The reason for enucleation in those two patients was intrascleral extension of the tumor and decreased vision. A summary of the pathologic findings is as follows. The melanoma location was peripapillary in one of seven cases, equatorial in two, and submacular in one. The melanoma cell type was mixed in all seven cases. Retinal atrophy and atrophy of the retinal pigment epithelium overlying the melanoma was present in all but one eye. There were areas of necrotic melanoma in cases 1, 2, 3, and 7. All eyes had histologically intact melanoma cells. The number of mitotic figures per 40 high-power fields in the melanomas ranged from 0 to 2 (median, 1; mean, 0.7). Four cases exhibited serous retinal detachment. Melanoma invasion within an emissary canal was present in all cases. This intrascleral extension had been detected by ultrasonography in four of the seven eyes. A peripheral choroidal nevus that was not clinically detected was histologically demonstrated in one eye (case 7). There was extrascleral extension of the melanoma in five of the seven eyes. Only one of the seven eyes (case 2) had extrascleral extension clinically detected by B-scan ultrasonography. Vortex vein invasion of melanoma was histologically found in three cases and invasion of the inferior oblique muscle was present in one case (case 6).
ogy Laboratory between 1998 and 2002 revealed seven eyes of seven patients that were enucleated after failed TTT without any other therapy to the choroidal melanoma. A chart review of the cases was used to summarize and record clinical visits and findings, including visual acuity, fundus appearance, ultrasonography (A- and Bscan), chest radiograph, computed tomography, and laboratory evaluation for metastasis. The TTT variables were recorded. The laser for the TTT for all cases was an iris diode laser (Iridex, Mountain View, California, USA) with a wavelength of 810 nm. The tumor size was monitored by standardized A- and B-scan ultrasonography, serial fundus photography, and clinical examination. The enucleated eyes were submitted in 10% neutral buffered formalin, grossly examined, and sectioned so that the maximum height of the tumor was in the same plane as the center of the pupil and optic nerve. The eye was routinely processed with increasing grades of alcohol, cleared with xylene, and embedded in paraffin, and 5-m sections were cut and stained with hematoxylin and eosin, as well as bleached with potassium permanganate. The eyes were studied with an Olympus BHTU microscope (Olympus, Tokyo, Japan), and the maximum size of the tumor, pathologic features including growth pattern, and presence or absence of extrascleral extension were recorded.
RESULTS THE CLINICAL AND PATHOLOGIC FINDINGS ARE SUMMA-
rized in Tables 1 and 2, respectively. There were six men and one woman, ranging in age from 36 to 65 years. This represented seven of 84 (8%) patients treated with TTT for choroidal melanoma during the period studied. A summary of the clinical findings is as follows. All patients who were enucleated had progressively decreasing vision or continued tumor growth, or both, in one or more planes (basal diameter, height, and scleral extension), as measured by ultrasonography. Six of the seven enucleated eyes had preoperative ultrasonographic or funduscopic evidence of increase in tumor height or basal diameter, in addition to decreased visual acuity. The remaining eye was enucleated, owing to decreased visual acuity and the patient’s request for enucleation. The height of the tumors ranged from 1.7 mm to 4.6 mm before TTT and from 0.6 to 2.8 mm after TTT. Before TTT, six of seven patients were found to have subretinal fluid, although the height of the fluid was not measured. The number of TTT sessions per patient ranged from one to four. The TTT laser power ranged from 300 to 1300 mW, depending on the pigmentation of the tumor and degree of cataract. The time interval between the last TTT and enucleation ranged between 3 and 19 months (median, 5; mean, 6.8). Intrascleral extension was detected by B-scan in four patients (patients 4 through 7) during the initial clinic visit, although it was not detected after treatment in two of 658
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CASE REPORTS THE FOLLOWING ARE ILLUSTRATIVE SUMMARIES OF REPRE-
sentative cases. ● CASE 1: A 48-year-old man was evaluated for a choroidal mass located at the equator (Figure 1, top left). The patient had suspected choriodal melanoma and associated scleritis with B-scan examination showing scleral thickening and fluid in the Tenon capsule. The patient refused brachytherapy or enucleation. The patient underwent one treatment with TTT and was placed on corticosteroids for treatment of the scleritis. Follow-up B-scan examination showed continued growth of the tumor in basal diameter, continued presence of fluid in the Tenon capsule, and increasing pain (Figure 1, top right). The patient consented to enucleation. The eye was found to have a malignant melanoma, mixed cell type, straddling the OF
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VOL. 135, NO. 5 TABLE 1. Clinical Findings
CHOROIDAL MELANOMAS AFTER FAILED THERMOTHERAPY
Patient Number
Age
Sex
1
48
M
2
57
M
3
53
M
4
54
M
5
65
M
6
36
M
7
56
F
VA at Time of Enucleation
Change in Basal Diameter From Presentation to Enucleation
Change in Height From Presentation to Enucleation
OD: 20/30 OS: 20/400 OD: 20/25 OS: 20/400 OD: 20/20 OS: 20/200 OD: 20/25 OS: 20/400 OD: 20/400 OS: 20/20 OD: 20/20
Initial: 11.9 mm ⫻ 12.2 mm Initial: 1.7 mm Enucleation: 12.9 mm ⫻ 15.8 mm Enucleation: 1.6 mm Initial: 9.1 mm ⫻ 10.2 mm Initial: 2.9 mm Enucleation: 12.8 mm ⫻ 11.1 mm Enucleation: 1.7 mm n/a Initial: 2.07 mm Enucleation: n/a Initial: 10.1 mm ⫻ 13.8 mm Initial: 2.4 mm Enucleation: 9.7 mm ⫻ 10.9 mm Enucleation: 2.6 mm Initial: 3.9 mm ⫻ 6.3 mm Initial: 1.7 mm Enucleation: 8.4 mm ⫻ 10.2 mm Enucleation: 2.8 mm Initial: 4.2 mm ⫻ 6.3 mm Initial: 2.7 mm
OS: HM OD: 20/60 OS: 20/20
Enucleation: 2.5 mm ⫻ 1.8 mm Initial: 8.4 mm ⫻ 12.0 mm Enucleation: 4.7 mm ⫻ 4.9 mm
Enucleation: 1.0 mm Initial: 4.6 mm Enucleation: 0.6 mm
Spot Size (mm)
TTT Power (mW)
Number TTT
Clinical Detection of Intrascleral Extension
Detection of Extrascleral Extension (Clinical or Pathological)
Time Interval Between Last TTT and Enucleation
Time Interval Between Presentation and Enucleation
SRF
3
500–900
1
—
E‡
5 months
6 months
⫹
3
500–1300
4
—
E†
3 months
28 months
⫹
3
500–700
2
—
—
7 months
24 months
⫹
3
700–900
1
I* (again†)
—
4 months
5 months
⫹
3
500–700
1
I* (not again)
E‡
19 months 30 months
⫹
3
300–800
2
I* (again 7 months later and persisted)
E‡
7 months
24 months
⫺
3
300–800
3
I* (not again)
E‡
3 months
19 months
⫹
E ⫽ extrascleral; F ⫽ female; HM ⫽ hand motions; I ⫽ intrascleral; M ⫽ male; n/a ⫽ not applicable; OD ⫽ right eye; OS ⫽ left eye; SRF ⫽ subretinal fluid; TTT ⫽ transpupillary thermotherapy; VA ⫽ visual acuity. * At initial B-scan ultrasonography. † By B-scan just prior to enucleation. ‡ Histopathologic diagnosis.
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TABLE 2. Pathologic Findings
Patient Number
Melanoma Location
Melanoma Pigmentation
Mitotic Figures (40 h.p.f.)
Melanoma Necrosis
Optic Nerve Invasion
Emissary Canal Invasion
Extrascleral Extension
Vortex Vein Invasion
Inflammation Signs
Cell Type
1 2 3 4 5 6 7
E P P E P M P
⫹ ⫹ ⫹⫹ ⫹⫹ ⫹ ⫹ ⫹⫹⫹
1 1 0 1 2 0 0
⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫹
⫺ ⫹ ⫺ ⫺ ⫹ ⫺ ⫹
⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹
⫹ ⫹ ⫺ ⫺ ⫹ ⫹ ⫹
⫹ ⫹ ⫺ ⫺ ⫹ ⫺ ⫺
⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺
Mixed Mixed Mixed Mixed Mixed Mixed Mixed
E ⫽ equatorial; h.p.f. ⫽ high-power fluids; M ⫽ Macular; P ⫽ peripapillary; ⫹ ⫽ minimal; ⫹⫹ ⫽ moderate; ⫹⫹⫹ ⫽ heavy.
FIGURE 1. Case 1. (Top left) An inferior equatorial melanoma is present. (Top right) B-scan shows melanoma, associated serous retinal detachment, and underlying slcera (arrow). (Bottom left) There is an equatorial melanoma with an overlying serous retinal detachment present. (hematoxylin and eosin, ⴛ5.) (Bottom right) Melanoma cells are present in a vortex vein. (hematoxylin and eosin, ⴛ100.)
equator (Figure 1, bottom left). Intact melanoma cells were also found in the lumen of the inferonasal vortex vein (Figure 1, bottom right).
top left). The basal diameter of the melanoma grew again to a greater extent and more rapidly than its height. In addition, the time interval between each subsequent TTT and evidence of regrowth, particularly the basal diameter, decreased over the 28-month period from initial evaluation to enucleation. There was no evidence of intrascleral or extrascleral extension of the tumor initially, although ultrasonography showed a bilobed, peripapillary lesion with an echolucent area posterior to the sclera suggestive of extrascleral extension (Figure 2, top right). This corresponded with the pathologic finding of a nodule of tumor
● CASE 2: A 57-year-old man with a choroidal melanoma located posterior to the equator underwent four treatments with TTT. Within 8 months of the first treatment, the melanoma was found to be flat on fundus and B-scan examination. The melanoma eventually grew again, and despite three more TTT treatments (total four treatments), it extended to a peripapillary location (Figure 2,
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FIGURE 2. Case 2. (Top left) This melanoma has had four TTTs and extends to the optic nerve. (Top right) B-scan shows an echolucent scleral/episcleral nodule (arrow). (Bottom left) There is a peripapillary melanoma present with extension through a posterior ciliary vein. (hematoxylin and eosin, ⴛ5.) (Bottom right) There is a nodule of melanoma in ciliary vein on the scleral surface. (hematoxylin and eosin, ⴛ25.)
filling a short posterior ciliary vein (Figure 2, bottom panels). ● CASE 6: A 36-year-old man had a choroidal melanoma located under the macula. Initial B-scan ultrasonography detected intrascleral tumor extension. The patient underwent two TTT treatments (Figure 3, top left). B-scan ultrasonography after the second treatment again showed intrascleral extension. Despite tumor regression over the 24-month period from presentation to enucleation, persistent ultrasound detection of intrascleral tumor spread (Figure 3, top right), and a visual acuity of hand motions led the patient to elect enucleation. Histopathologic examination of the enucleated eye showed intrascleral and extrascleral extension of the melanoma (Figure 3, bottom left) into the tendon and muscle fibers of the inferior oblique (Figure 3, bottom right).
DISCUSSION THERE HAS BEEN A DECREASE IN THE NUMBER OF ENUCLE-
ations performed for melanoma over the past several decades from approximately 71% in 1971 to 21% in 1991.21–23 This has been due largely to eye salvaging therapies for melanoma control. Eye salvaging therapies include radioactive plaque therapy, radiotherapy with VOL. 135, NO. 5
charged particles, laser photocoagulation, TTT, local resection, and combined treatments.3– 8 The popularity of TTT has increased because of a reduction in tumor thickness to a flat scar, which has been achieved in more than 90% of cases with miminal complications.13,15,16,24 –27 The pathology of experimentally induced tissue hyperthermia has been studied.17,18 Those studies showed tumor necrosis within 6 weeks after TTT in 13 of 15 cases. There is a group of patients whose tumors do not respond to TTT and eventually require enucleation. Two studies examined the histopathology of enucleated eyes after failed TTT in four patients.19,20 In one study, one tumor was incompletely treated because of opaque media, and the other melanoma recurred, owing to the aggressive nature of the tumor.20 In the other study, there were histologically intact melanoma cells adjacent to scleral emissary canals.19 Our study showed histologically intact melanoma cells in emissary canals in all seven eyes. In the largest histopathologic study of uveal melanoma to date, intrascleral and extrascleral tumor extension was present in 56% and 8% of enucleated eyes, respectively.28 This compares with 100% and 71% intrascleral and extrascleral tumor extension after failed TTT in our study. The presence of histologically intact, intrascleral melanoma cells has been postulated as the source of tumor recurrence after TTT.3 The ability of TTT to penetrate into the sclera is limited by the lack of absorption of
CHOROIDAL MELANOMAS AFTER FAILED THERMOTHERAPY
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FIGURE 3. Case 6. (Top left) The melanoma has had two TTT treatments. (Top right) B-scan shows intrascleral extension of the melanoma (arrow). (Bottom left) The melanoma directly extends through the sclera. (hematoxylin and eosin, ⴛ5.) (Bottom right) The melanoma invades muscle fibers of the inferior oblique. (hematoxylin and eosin, ⴛ100.)
path of least resistance. This means that the melanoma generally grows in a horizontal plane within the choroid and along emissary canals. The rate of enucleation after failed TTT was 8% in our series, comparable to the 12% enucleation rate after failed I125 plaque therapy.30 Transpupillary thermotherapy appears to fail for two main reasons. First, TTT may not destroy viable intrascleral melanoma cells and prevent extrascleral extension. Second, particularly aggressive tumor cells may resist repeated TTT. Two of our patients had decreased tumor size after TTT, as measured by ultrasonography, although they underwent enucleation because of intrascleral spread of the tumor. The remaining patients had continued tumor growth in the basal diameter or height, or both. The presence of intrascleral melanoma detected by B-scan before TTT treatment may be predictive of TTT failure. Patients in our study were treated with TTT prior to recognition that intrascleral melanoma demonstrated by B-scan is a contraindication for TTT.3 Researchers are studying transscleral thermotherapy (TSTT). Using parameters similar to TTT (810-nm diode laser, 1-minute applications, 3-mm spot size), the aim is to heat the sclera to destroy the feeder vessels of the melanoma as well as intrascleral melanoma cells. Initial results have shown melanoma necrosis to a depth of 4.4 mm without scleral damage.31,32 The clinical efficacy of TSTT remains to be determined.
infrared light in the sclera.3 In our cases 5 and 7, intrascleral extension of the melanoma was detected by B-scan ultrasonography at the initial presentation. After treatment with TTT, intrascleral extension was not detected by B-scan, although it was histologically demonstrated. Case 6 showed intrascleral extension detected by B-scan at the initial evaluation. The intrascleral extension was not visible after the initial TTT, although it was again detected 7 months later. Our study shows the important finding of a lack of clinical detection of extrascleral extension of choroidal melanoma after TTT. Only one case (case 2) had B-scan ultrasonographic evidence of extrascleral extension, although five cases had histologic evidence of extrascleral extension (cases 1, 2, 5, 6, and 7). The 10-year mortality rate nearly doubles if there is extrascleral melanoma extension versus if there is no extension.29 The growth pattern of the TTT-treated melanomas in our study differed from the growth pattern described in the Collaborative Ocular Melanoma Study (COMS).28 Vertical growth, with disruption of the Bruch membrane, was present in 88% of COMS eyes; however, in our series 86% of melanomas were confined by the Bruch membrane. That finding may be due to the generally smaller size of the melanomas in our study. Three of our cases exhibited relatively greater horizontal than vertical growth. It appears that the Bruch membrane and the sclera provide barriers. When the melanoma recurs, it grows along the 662
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Our study shows the important finding that extrascleral extension of melanoma occurred in five of seven eyes that failed TTT. The extrascleral extension was clinically detected by ultrasonography in only one of those five eyes. Extrascleral extension is associated with increased mortality. These findings need to be taken into account when planning local therapy for choroidal melanoma.
REFERENCES 1. Seregard S. Posterior uveal melanoma. Acta Ophthalmol Scand 1996;74:315–329. 2. Vidal J, Bacin F, Albuisson E, et al. “Melanoma 92”. Epidemiological study of uveal melanoma in France. J Fr Ophthalmol 1995;18:520 –528. 3. Journe´ e-de Korver J, Keunen J. Thermotherapy in the management of choroidal melanoma. Prog Retin Eye Res 2002;21:303–317. 4. Jensen O, Prause J, Scherfig E. Transvitreal retino-choroidal biopsy of suspected malignant lesions of the choroid. Follow-up of cases over 7 years. Acta Ophthalmol Scand 1997;75:409 –411. 5. De Potter P, Shields C, Shields J. New treatment modalities for uveal melanoma. Curr Opin Ophthalmol 1996;7:27–32. 6. Shields J, Shields C. Current management of posterior uveal melanoma. Mayo Clin Proc 1993;68:1196 –2000. 7. Billson F, Painter G, Dunlop I, Thomas R, Aylward G. The conservative management of choroidal melanoma. Aust N Z J Ophthalmol 1990;18:65–75. 8. Foulds W, Damato B. Alternatives to enucleation in the management of choroidal melanoma. Aust N Z J Ophthalmol 1986;14:19 –27. 9. Lommatzsch P, Kirsch I. Ru 106/Rh 106 plaque-radiotherapy for malignant melanomas of the choroid. Doc Ophthalmol 1988;68:225–238. 10. Finger P. Radiation therapy for choroidal melanoma. Surv Ophthalmol 1997;42:215–232. 11. Damato B, Paul J, Foulds W. Risk factors for residual and recurrent uveal melanoma after transscleral local resection. Br J Ophthalmol 1996;80:102–108. 12. Oosterhuis J, Journe´ e-de Korver H, Kakebeeke-Kemme H, Bleeker J. Transpupillary thermotherapy in choroidal melanomas. Arch Ophthalmol 1995;113:315–321. 13. Shields C, Shields J, Perez N, Singh A, Cater J. Primary transpupillary thermotherapy for choroidal melanoma in 256 consecutive cases: outcomes and limitations. Ophthalmology 2002;109:225–234. 14. Shields C, Shields J, DePotter P, Kheterpal S. Transpupillary thermotherapy in the management of choroidal melanoma. Ophthalmology 1996;103:1642–1650. 15. Shields C, Shields J, Cater J, et al. Transpupillary thermotherapy for choroidal melanoma: tumor control and visual results in 100 consecutive cases. Ophthalmology 1998;105: 581–590.
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16. Robertson D, Buettner H, Bennett S. Transpupillary thermotherapy as primary treatment for small choroidal melanomas. Arch Ophthalmol 1999;117:1512–1519. 17. Kociecki J, Biczysko W, Journe´ e-de Korver H, Keunen J, Pecold K. Additional cell damage after transpupillary thermotherapy in choroidal malignant melanoma. Melanoma Res 2001;11:511–515. 18. Journe´ e-de Korver J, Oosterhuis J, de Wolff-Rouendaal D. Histopathological findings in human choroidal melanomas after transpupillary thermotherapy. Br J Ophthalmol 1997; 81:234 –239. 19. Diaz C, Capone A, Grossniklaus H. Clinicopathologic findings in recurrent choroidal melanoma after transpupillary thermotherapy. Ophthalmology 1998;105:1419 –1424. 20. Finger P, Lipka A, Lipkowitz J, Jofe M, McCormick S. Failure of transpupillary thermotherapy (TTT) for choroidal melanoma: two cases with histopathological correlation. Br J Ophthalmol 2000;84:1075–1076. 21. Shields J, Shields C, Donoso L. Management of the posterior uveal melanoma. Surv Ophthalmol 1991;36:161–195. 22. Seregard S, Kock E. Prognostic indicators following enucleation for posterior uveal melanoma. Acta Ophthalmol Scand 1995;73:340 –344. 23. Seregard S. Posterior uveal melanoma. Acta Ophthalmol Scand 1996;74:315–329. 24. Keunen J, Bleeker J, Journe´ e-de Korver J, Oosterhuis J, van Best J. Juxtapapillary melanomas and transpupillary thermotherapy. Invest Ophthalmol Vis Sci 1997;38(Suppl):S720. 25. Shields C, Shields J, Gu¨ ndu¨ z F, Freire J, Mercado G. Radiation therapy for uveal malignant melanoma. Ophthalmic Surg Lasers 1998;29:397–409. 26. Schneider H, Fischer K, Fietkau R, Guthoff R. Transpupillary thermotherapy of choroidal melanoma. Klin Monatsbl Augenheilkd 1999;214:90 –95. 27. Godfrey D, Waldron R, Capone A. Transpupillary thermotherapy for small choroidal melanoma. Am J Ophthalmol 1999;128:88 –93. 28. Collaborative Ocular Melanoma Study Group. 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. 29. Seddon J, Albert D, Lavin P, et al. A prognostic factor study of diseases-free interval and survival following enucleation for uveal melanoma. Arch Ophthalmol 1983;101:1894 – 1899. 30. Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma III: initial mortality findings (COMS report no. 18). Arch Ophthalmol 2001;119:969 –982. 31. Rem A, Oosterhuis J, Journe´ e-de Korver J, van den Berg T, Keunen J. Temperature dependence of thermal damage to the sclera: exploring the heat tolerance of the sclera for transscleral thermotherapy. Exp Eye Res 2001;72:153–162. 32. Rem A, Oosterhuis J, Journe´ e-de Korver J, van den Berg T. Transscleral laser thermotherapy of hamster Greene melanoma: inducing tumour necrosis without scleral damage. Melanoma Res 2001;11:503–509.
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● PURPOSE: To review the clinicopathologic features of eyes enucleated after failed transpupillary thermotherapy. ● DESIGN: Retrospective review. ● METHODS: Pathology reports in the L.F. Montgomery Laboratory between 1998 and 2002 were searched for enucleated eyes with choroidal melanoma that had been treated only by transpupillary thermotherapy (TTT) prior to enucleation. The clinical features of the patients, including ultrasonography examination, were reviewed and compared with the pathologic findings. ● RESULTS: Seven eyes from seven patients had been enucleated, representing 8% of eyes treated with TTT at our institute during the period studied. The primary indication for enucleation was tumor growth. The melanomas tended to grow laterally, with minimal if any increase in thickness. Five of the seven eyes histologically demonstrated extrascleral extension, which was detected by ultrasonography prior to enucleation in only one of those eyes. ● CONCLUSIONS: Choroidal melanoma may continue to grow along a path of least resistance after TTT. The melanoma may extend laterally in the choroid and through emissary canals. Early extrascleral extension may be difficult to detect by ultrasonography. (Am J Ophthalmol 2003;135:657– 663. © 2003 by Elsevier Inc. All rights reserved.)
U
VEAL MELANOMA IS THE MOST COMMON PRIMARY
intraocular malignancy with an annual incidence of 6 to 8 per million population.1,2 The choroid is the most common part of the uveal tract that gives rise to melanoma. Over the past several decades, numerous eye-
Accepted for publication Nov 25, 2002. From the Department of Ophthalmology (R.A.Z., P.S., R.W., H.E.G.), Emory University, Atlanta, Georgia and Associated Retinal Consultants (T.M.A.), Grand Rapids, Michigan. Supported in part by an unrestricted department grant from Research to Prevent Blindness, Inc, New York, New York. Inquiries to Hans E. Grossniklaus MD, L.F. Montgomery Ophthalmic Pathology Laboratory, BT 428 Emory Eye Center, 1365 Clifton Rd, Atlanta, GA 30322; e-mail: [email protected] 0002-9394/03/$30.00 doi:10.1016/S0002-9394(02)02171-2
©
2003 BY
salvaging therapies for uveal melanoma have been developed. Conservative treatment modalities have included radioactive plaque, local resection, and various heatproducing methods.3– 8 Radioactive plaque therapy has been shown to stabilize or reduce melanoma size in more than 90% of cases, although 40% of plaqued eyes develop radiation complications.9,10 Transscleral resection of choroidal melanoma has been performed for more than a decade, although complication rates are greater than 20%.3,11 Heat-inducing methods include photocoagulation (⬎65 C), hyperthermia (44 C), and thermotherapy (45 to 65 C).3 Heat-inducing methods, either alone or in combination with other treatments, have recently received much attention. Transpupillary thermotherapy (TTT) has shown evidence of clinically decreasing tumor size with few complications.3,12–16 Transpupillary thermotherapy uses infrared light produced by a diode laser (810 nm) to induce tissue hyperthermia (45 C to 65 C). The laser is focused through the dilated pupil onto the tumor with the spot size ranging from 2 to 3 mm and an exposure time of 1 minute. At this temperature and with exposure time, tumor size has been shown to progressively decrease, even after only one treatment.16 The early histopathologic effects of experimental TTT have been described.17,18 Two studies examined the histopathologic effects after failed TTT in four eyes.19,20 In this study, we report the histopathologic features in seven eyes of seven patients who underwent enucleation after failed TTT. We correlated the pathologic findings with preoperative clinical findings, including the ultrasound appearance of the melanomas.
METHODS THE INSTITUTIONAL REVIEW BOARD OF EMORY UNIVERSITY
approved the study, including a retrospective chart review and correlation with histopathologic findings. A review of the diagnoses in the L.F. Montgomery Ophthalmic Pathol-
ELSEVIER INC. ALL
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those patients. There was histologic evidence of intrascleral extension in all four patients. Only one patient had B-scan ultrasonographic evidence of extrascleral extension before enucleation (patient 2). In addition to that case, four additional eyes were histologically found to exhibit extrascleral extension of the melanoma (patients 1, 5, 6, and 7). Tumor growth in basal diameter occurred in three patients, and one patient exhibited growth in both basal diameter and height. The percent increase in basal diameter exceeded the percent increase in height in this patient. Two patients exhibited a decrease in tumor basal diameter and height. The reason for enucleation in those two patients was intrascleral extension of the tumor and decreased vision. A summary of the pathologic findings is as follows. The melanoma location was peripapillary in one of seven cases, equatorial in two, and submacular in one. The melanoma cell type was mixed in all seven cases. Retinal atrophy and atrophy of the retinal pigment epithelium overlying the melanoma was present in all but one eye. There were areas of necrotic melanoma in cases 1, 2, 3, and 7. All eyes had histologically intact melanoma cells. The number of mitotic figures per 40 high-power fields in the melanomas ranged from 0 to 2 (median, 1; mean, 0.7). Four cases exhibited serous retinal detachment. Melanoma invasion within an emissary canal was present in all cases. This intrascleral extension had been detected by ultrasonography in four of the seven eyes. A peripheral choroidal nevus that was not clinically detected was histologically demonstrated in one eye (case 7). There was extrascleral extension of the melanoma in five of the seven eyes. Only one of the seven eyes (case 2) had extrascleral extension clinically detected by B-scan ultrasonography. Vortex vein invasion of melanoma was histologically found in three cases and invasion of the inferior oblique muscle was present in one case (case 6).
ogy Laboratory between 1998 and 2002 revealed seven eyes of seven patients that were enucleated after failed TTT without any other therapy to the choroidal melanoma. A chart review of the cases was used to summarize and record clinical visits and findings, including visual acuity, fundus appearance, ultrasonography (A- and Bscan), chest radiograph, computed tomography, and laboratory evaluation for metastasis. The TTT variables were recorded. The laser for the TTT for all cases was an iris diode laser (Iridex, Mountain View, California, USA) with a wavelength of 810 nm. The tumor size was monitored by standardized A- and B-scan ultrasonography, serial fundus photography, and clinical examination. The enucleated eyes were submitted in 10% neutral buffered formalin, grossly examined, and sectioned so that the maximum height of the tumor was in the same plane as the center of the pupil and optic nerve. The eye was routinely processed with increasing grades of alcohol, cleared with xylene, and embedded in paraffin, and 5-m sections were cut and stained with hematoxylin and eosin, as well as bleached with potassium permanganate. The eyes were studied with an Olympus BHTU microscope (Olympus, Tokyo, Japan), and the maximum size of the tumor, pathologic features including growth pattern, and presence or absence of extrascleral extension were recorded.
RESULTS THE CLINICAL AND PATHOLOGIC FINDINGS ARE SUMMA-
rized in Tables 1 and 2, respectively. There were six men and one woman, ranging in age from 36 to 65 years. This represented seven of 84 (8%) patients treated with TTT for choroidal melanoma during the period studied. A summary of the clinical findings is as follows. All patients who were enucleated had progressively decreasing vision or continued tumor growth, or both, in one or more planes (basal diameter, height, and scleral extension), as measured by ultrasonography. Six of the seven enucleated eyes had preoperative ultrasonographic or funduscopic evidence of increase in tumor height or basal diameter, in addition to decreased visual acuity. The remaining eye was enucleated, owing to decreased visual acuity and the patient’s request for enucleation. The height of the tumors ranged from 1.7 mm to 4.6 mm before TTT and from 0.6 to 2.8 mm after TTT. Before TTT, six of seven patients were found to have subretinal fluid, although the height of the fluid was not measured. The number of TTT sessions per patient ranged from one to four. The TTT laser power ranged from 300 to 1300 mW, depending on the pigmentation of the tumor and degree of cataract. The time interval between the last TTT and enucleation ranged between 3 and 19 months (median, 5; mean, 6.8). Intrascleral extension was detected by B-scan in four patients (patients 4 through 7) during the initial clinic visit, although it was not detected after treatment in two of 658
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CASE REPORTS THE FOLLOWING ARE ILLUSTRATIVE SUMMARIES OF REPRE-
sentative cases. ● CASE 1: A 48-year-old man was evaluated for a choroidal mass located at the equator (Figure 1, top left). The patient had suspected choriodal melanoma and associated scleritis with B-scan examination showing scleral thickening and fluid in the Tenon capsule. The patient refused brachytherapy or enucleation. The patient underwent one treatment with TTT and was placed on corticosteroids for treatment of the scleritis. Follow-up B-scan examination showed continued growth of the tumor in basal diameter, continued presence of fluid in the Tenon capsule, and increasing pain (Figure 1, top right). The patient consented to enucleation. The eye was found to have a malignant melanoma, mixed cell type, straddling the OF
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VOL. 135, NO. 5 TABLE 1. Clinical Findings
CHOROIDAL MELANOMAS AFTER FAILED THERMOTHERAPY
Patient Number
Age
Sex
1
48
M
2
57
M
3
53
M
4
54
M
5
65
M
6
36
M
7
56
F
VA at Time of Enucleation
Change in Basal Diameter From Presentation to Enucleation
Change in Height From Presentation to Enucleation
OD: 20/30 OS: 20/400 OD: 20/25 OS: 20/400 OD: 20/20 OS: 20/200 OD: 20/25 OS: 20/400 OD: 20/400 OS: 20/20 OD: 20/20
Initial: 11.9 mm ⫻ 12.2 mm Initial: 1.7 mm Enucleation: 12.9 mm ⫻ 15.8 mm Enucleation: 1.6 mm Initial: 9.1 mm ⫻ 10.2 mm Initial: 2.9 mm Enucleation: 12.8 mm ⫻ 11.1 mm Enucleation: 1.7 mm n/a Initial: 2.07 mm Enucleation: n/a Initial: 10.1 mm ⫻ 13.8 mm Initial: 2.4 mm Enucleation: 9.7 mm ⫻ 10.9 mm Enucleation: 2.6 mm Initial: 3.9 mm ⫻ 6.3 mm Initial: 1.7 mm Enucleation: 8.4 mm ⫻ 10.2 mm Enucleation: 2.8 mm Initial: 4.2 mm ⫻ 6.3 mm Initial: 2.7 mm
OS: HM OD: 20/60 OS: 20/20
Enucleation: 2.5 mm ⫻ 1.8 mm Initial: 8.4 mm ⫻ 12.0 mm Enucleation: 4.7 mm ⫻ 4.9 mm
Enucleation: 1.0 mm Initial: 4.6 mm Enucleation: 0.6 mm
Spot Size (mm)
TTT Power (mW)
Number TTT
Clinical Detection of Intrascleral Extension
Detection of Extrascleral Extension (Clinical or Pathological)
Time Interval Between Last TTT and Enucleation
Time Interval Between Presentation and Enucleation
SRF
3
500–900
1
—
E‡
5 months
6 months
⫹
3
500–1300
4
—
E†
3 months
28 months
⫹
3
500–700
2
—
—
7 months
24 months
⫹
3
700–900
1
I* (again†)
—
4 months
5 months
⫹
3
500–700
1
I* (not again)
E‡
19 months 30 months
⫹
3
300–800
2
I* (again 7 months later and persisted)
E‡
7 months
24 months
⫺
3
300–800
3
I* (not again)
E‡
3 months
19 months
⫹
E ⫽ extrascleral; F ⫽ female; HM ⫽ hand motions; I ⫽ intrascleral; M ⫽ male; n/a ⫽ not applicable; OD ⫽ right eye; OS ⫽ left eye; SRF ⫽ subretinal fluid; TTT ⫽ transpupillary thermotherapy; VA ⫽ visual acuity. * At initial B-scan ultrasonography. † By B-scan just prior to enucleation. ‡ Histopathologic diagnosis.
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TABLE 2. Pathologic Findings
Patient Number
Melanoma Location
Melanoma Pigmentation
Mitotic Figures (40 h.p.f.)
Melanoma Necrosis
Optic Nerve Invasion
Emissary Canal Invasion
Extrascleral Extension
Vortex Vein Invasion
Inflammation Signs
Cell Type
1 2 3 4 5 6 7
E P P E P M P
⫹ ⫹ ⫹⫹ ⫹⫹ ⫹ ⫹ ⫹⫹⫹
1 1 0 1 2 0 0
⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫹
⫺ ⫹ ⫺ ⫺ ⫹ ⫺ ⫹
⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹
⫹ ⫹ ⫺ ⫺ ⫹ ⫹ ⫹
⫹ ⫹ ⫺ ⫺ ⫹ ⫺ ⫺
⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺
Mixed Mixed Mixed Mixed Mixed Mixed Mixed
E ⫽ equatorial; h.p.f. ⫽ high-power fluids; M ⫽ Macular; P ⫽ peripapillary; ⫹ ⫽ minimal; ⫹⫹ ⫽ moderate; ⫹⫹⫹ ⫽ heavy.
FIGURE 1. Case 1. (Top left) An inferior equatorial melanoma is present. (Top right) B-scan shows melanoma, associated serous retinal detachment, and underlying slcera (arrow). (Bottom left) There is an equatorial melanoma with an overlying serous retinal detachment present. (hematoxylin and eosin, ⴛ5.) (Bottom right) Melanoma cells are present in a vortex vein. (hematoxylin and eosin, ⴛ100.)
equator (Figure 1, bottom left). Intact melanoma cells were also found in the lumen of the inferonasal vortex vein (Figure 1, bottom right).
top left). The basal diameter of the melanoma grew again to a greater extent and more rapidly than its height. In addition, the time interval between each subsequent TTT and evidence of regrowth, particularly the basal diameter, decreased over the 28-month period from initial evaluation to enucleation. There was no evidence of intrascleral or extrascleral extension of the tumor initially, although ultrasonography showed a bilobed, peripapillary lesion with an echolucent area posterior to the sclera suggestive of extrascleral extension (Figure 2, top right). This corresponded with the pathologic finding of a nodule of tumor
● CASE 2: A 57-year-old man with a choroidal melanoma located posterior to the equator underwent four treatments with TTT. Within 8 months of the first treatment, the melanoma was found to be flat on fundus and B-scan examination. The melanoma eventually grew again, and despite three more TTT treatments (total four treatments), it extended to a peripapillary location (Figure 2,
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FIGURE 2. Case 2. (Top left) This melanoma has had four TTTs and extends to the optic nerve. (Top right) B-scan shows an echolucent scleral/episcleral nodule (arrow). (Bottom left) There is a peripapillary melanoma present with extension through a posterior ciliary vein. (hematoxylin and eosin, ⴛ5.) (Bottom right) There is a nodule of melanoma in ciliary vein on the scleral surface. (hematoxylin and eosin, ⴛ25.)
filling a short posterior ciliary vein (Figure 2, bottom panels). ● CASE 6: A 36-year-old man had a choroidal melanoma located under the macula. Initial B-scan ultrasonography detected intrascleral tumor extension. The patient underwent two TTT treatments (Figure 3, top left). B-scan ultrasonography after the second treatment again showed intrascleral extension. Despite tumor regression over the 24-month period from presentation to enucleation, persistent ultrasound detection of intrascleral tumor spread (Figure 3, top right), and a visual acuity of hand motions led the patient to elect enucleation. Histopathologic examination of the enucleated eye showed intrascleral and extrascleral extension of the melanoma (Figure 3, bottom left) into the tendon and muscle fibers of the inferior oblique (Figure 3, bottom right).
DISCUSSION THERE HAS BEEN A DECREASE IN THE NUMBER OF ENUCLE-
ations performed for melanoma over the past several decades from approximately 71% in 1971 to 21% in 1991.21–23 This has been due largely to eye salvaging therapies for melanoma control. Eye salvaging therapies include radioactive plaque therapy, radiotherapy with VOL. 135, NO. 5
charged particles, laser photocoagulation, TTT, local resection, and combined treatments.3– 8 The popularity of TTT has increased because of a reduction in tumor thickness to a flat scar, which has been achieved in more than 90% of cases with miminal complications.13,15,16,24 –27 The pathology of experimentally induced tissue hyperthermia has been studied.17,18 Those studies showed tumor necrosis within 6 weeks after TTT in 13 of 15 cases. There is a group of patients whose tumors do not respond to TTT and eventually require enucleation. Two studies examined the histopathology of enucleated eyes after failed TTT in four patients.19,20 In one study, one tumor was incompletely treated because of opaque media, and the other melanoma recurred, owing to the aggressive nature of the tumor.20 In the other study, there were histologically intact melanoma cells adjacent to scleral emissary canals.19 Our study showed histologically intact melanoma cells in emissary canals in all seven eyes. In the largest histopathologic study of uveal melanoma to date, intrascleral and extrascleral tumor extension was present in 56% and 8% of enucleated eyes, respectively.28 This compares with 100% and 71% intrascleral and extrascleral tumor extension after failed TTT in our study. The presence of histologically intact, intrascleral melanoma cells has been postulated as the source of tumor recurrence after TTT.3 The ability of TTT to penetrate into the sclera is limited by the lack of absorption of
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FIGURE 3. Case 6. (Top left) The melanoma has had two TTT treatments. (Top right) B-scan shows intrascleral extension of the melanoma (arrow). (Bottom left) The melanoma directly extends through the sclera. (hematoxylin and eosin, ⴛ5.) (Bottom right) The melanoma invades muscle fibers of the inferior oblique. (hematoxylin and eosin, ⴛ100.)
path of least resistance. This means that the melanoma generally grows in a horizontal plane within the choroid and along emissary canals. The rate of enucleation after failed TTT was 8% in our series, comparable to the 12% enucleation rate after failed I125 plaque therapy.30 Transpupillary thermotherapy appears to fail for two main reasons. First, TTT may not destroy viable intrascleral melanoma cells and prevent extrascleral extension. Second, particularly aggressive tumor cells may resist repeated TTT. Two of our patients had decreased tumor size after TTT, as measured by ultrasonography, although they underwent enucleation because of intrascleral spread of the tumor. The remaining patients had continued tumor growth in the basal diameter or height, or both. The presence of intrascleral melanoma detected by B-scan before TTT treatment may be predictive of TTT failure. Patients in our study were treated with TTT prior to recognition that intrascleral melanoma demonstrated by B-scan is a contraindication for TTT.3 Researchers are studying transscleral thermotherapy (TSTT). Using parameters similar to TTT (810-nm diode laser, 1-minute applications, 3-mm spot size), the aim is to heat the sclera to destroy the feeder vessels of the melanoma as well as intrascleral melanoma cells. Initial results have shown melanoma necrosis to a depth of 4.4 mm without scleral damage.31,32 The clinical efficacy of TSTT remains to be determined.
infrared light in the sclera.3 In our cases 5 and 7, intrascleral extension of the melanoma was detected by B-scan ultrasonography at the initial presentation. After treatment with TTT, intrascleral extension was not detected by B-scan, although it was histologically demonstrated. Case 6 showed intrascleral extension detected by B-scan at the initial evaluation. The intrascleral extension was not visible after the initial TTT, although it was again detected 7 months later. Our study shows the important finding of a lack of clinical detection of extrascleral extension of choroidal melanoma after TTT. Only one case (case 2) had B-scan ultrasonographic evidence of extrascleral extension, although five cases had histologic evidence of extrascleral extension (cases 1, 2, 5, 6, and 7). The 10-year mortality rate nearly doubles if there is extrascleral melanoma extension versus if there is no extension.29 The growth pattern of the TTT-treated melanomas in our study differed from the growth pattern described in the Collaborative Ocular Melanoma Study (COMS).28 Vertical growth, with disruption of the Bruch membrane, was present in 88% of COMS eyes; however, in our series 86% of melanomas were confined by the Bruch membrane. That finding may be due to the generally smaller size of the melanomas in our study. Three of our cases exhibited relatively greater horizontal than vertical growth. It appears that the Bruch membrane and the sclera provide barriers. When the melanoma recurs, it grows along the 662
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Our study shows the important finding that extrascleral extension of melanoma occurred in five of seven eyes that failed TTT. The extrascleral extension was clinically detected by ultrasonography in only one of those five eyes. Extrascleral extension is associated with increased mortality. These findings need to be taken into account when planning local therapy for choroidal melanoma.
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