- Email: [email protected]
Histopathology of eyes enucleated after endoresection of choroidal melanoma
Histopathology of Eyes Enucleated after Endoresection of Choroidal Melanoma Peter W. Hadden, MBChB, FRANZCO, Paul S. Hiscott, PhD, FRCPath, Bertil E. Damato, MD, FRCOphth Purpose: To demonstrate the histopathologic features of eyes enucleated after endoresection for choroidal melanoma to assess the complications of this treatment and to determine indications for further treatment after endoresection in the setting of possible tumor recurrence. Design: Retrospective, observational case series. Participants: Sixty-one consecutive patients who had undergone endoresection for uveal melanoma. Methods: Eyes that had undergone enucleation after endoresection were identified, and their charts and histologic characteristics were reviewed. Pertinent features were described. One patient was excluded because enucleation was performed as a primary treatment when endoresection was abandoned at the time of his initial treatment. Main Outcome Measures: The outcome measures included: reasons for enucleation; tumor recurrence; and location, clinical, and histologic characteristics of each recurrence. Results: Twelve eyes were identified that had undergone enucleation after endoresection. The reasons for enucleation were: (1) local tumor recurrence detected by ophthalmoscopy (2 patients) or echography (1 patient); (2) opaque media preventing adequate ophthalmoscopy (4 patients); (3) blind and painful eye of uncertain cause (1 patient); and (4) a combination of blind eye and limited fundus view (4 patients), which was the result of untreatable retinal detachment (3 patients) and endophthalmitis (1 patient). Eight of 12 patients had recurrent choroidal melanoma. Recurrences were all located adjacent to the resection site, although in 1 patient there was extensive diffuse recurrence throughout the eye. The recurrence was visible clinically in 3 patients and obscured because of opaque media (2 patients), a combination of inadequate echography and retinal detachment (1 patient), retinal detachment (1 patient), and endophthalmitis (1 patient). Conclusions: Recurrent disease occurred at the site of the primary tumor with no seeding except in 1 patient, whose marginal recurrence was not immediately detected and treated because of opaque media. As with other treatments conserving the eye, enucleation should be performed if adequate ocular examination is not possible, and follow-up should be lifelong. Ophthalmology 2004;111:154 –160 © 2004 by the American Academy of Ophthalmology.
Uveal melanoma, although a relatively rare disease, is the most common primary intraocular malignancy, with an incidence of 6 to 7 per 1 million per year.1,2 Of these tumors, 80% are choroidal. The treatment of choroidal melanoma may be either radical (i.e., enucleation) or aimed at conserving the eye with as much vision as possible (i.e., conservative treatment). Conservative treatment of choroidal melanoma includes radiotherapy, phototherapy, and local resection. Radiotherapy has been shown to be as effective as enucleation in Originally received: August 1, 2002. Accepted: May 5, 2003. Manuscript no. 220528. From the Liverpool Ocular Oncology Centre, St. Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom. Correspondence to Dr Peter W. Hadden, Liverpool Ocular Oncology Centre, St. Paul’s Eye Unit, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, United Kingdom. E-mail: peterandandy@ hotmail.com. Reprint requests to Bertil E. Damato, Liverpool Ocular Oncology Centre, St. Paul’s Eye Unit, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, United Kingdom. E-mail: Bertil.Damato@ BTInternet.com.
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© 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
preventing mortality from medium-sized choroidal melanomas3 and is the most common first-line treatment. It usually is delivered with ruthenium or iodine plaque brachytherapy, but also may be given by charged particles or in the form of stereotactic radiotherapy. Photocoagulation largely has been superseded by transpupillary thermotherapy (TTT). Because TTT is a relatively recent innovation, long-term results are not yet available.4 Endoresection, described in detail by Damato et al,5 was developed in an attempt to overcome the limitations of radiotherapy options for juxtapapillary lesions. It is used most often in cases in which a choroidal melanoma extends within 1 disc diameter of the optic nerve, or in cases of recurrent tumor after other forms of treatment. It is not at present considered (1) for tumors that involve more than one third of the disc margin, because the prognosis for vision in such cases is limited, (2) for diffuse tumors, or (3) for those with a basal diameter more than 10 to 11 mm. If there is any question regarding the adequacy of tumor resection, adjunctive plaque brachytherapy may be used. Transpupillary thermotherapy also can be administered, either before or after surgery. ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.05.007
Hadden et al 䡠 Histopathology of Endoresection Table 1. Clinical Features at Endoresection
Patient No. 1 2 3 4 5 6 7 8 9 10 11 12
Age (yrs)
Gender
Eye
Location with Respect to Optic Disc
67 81 40 25 56 51 76 60 61 44 46 45
F F M F F M M F F M M F
R R R L L L L L L R R L
Inferior Inferior Inferior Inferonasal Nasal Inferonasal Superonasal Nasal Temporal Inferonasal Superior Temporal
Largest Basal Diameter 11.0 mm 5.2 mm 12.0 mm 9.0 mm 6.1 mm 11.6 mm 8.8 mm 10.0 mm 5.0 mm 8.0 mm 9.9 mm 5.2 mm
Thickness 6.5 1.9 4.8 4.0 3.0 7.2 5.0 2.0 4.0 2.4 6.7 2.3
mm mm mm mm mm mm mm mm mm mm mm mm
Distance to Disc
Amount of Disc Margin Involved*
Tumor Cell Type
0 mm ⬍1 DD ⬍1 DD Macula 0 mm 0 mm 0 mm ⬍1 DD 0 mm ⬍1 DD Equator 0 mm
3 Nil Nil Nil 2 1 1 Nil 4 Nil Nil 1
Spindle Spindle† Mixed Unknown‡ Spindle Mixed Epithelioid Mixed Epithelioid Spindle Mixed Spindle
F ⫽ female; L ⫽ left; M ⫽ male; R ⫽ right. *In clock hours. † Only one small fragment of tumor, specimen too small to confirm malignancy absolutely by cytologic or histologic criteria. ‡ No histologic results available.
Endoresection of choroidal melanoma is controversial because of fears that piecemeal tumor removal would result in tumor seeding around the eye; therefore, it is performed only in a few centers, where it is reserved for patients in whom preservation of vision is important in the tumoraffected eye. The aim of this study was to demonstrate the histopathologic features of eyes enucleated after endoresection to determine the frequency of subclinical, microscopic, residual tumor both at the site of the coloboma and in other parts of the eye.
Materials and Methods All patients undergoing endoresection at the Royal Liverpool University Hospital between January 1, 1993 and February 28, 2002 were identified retrospectively using a computer database. The technique of endoresection used in this study has been described previously.5 Eyes were enucleated at the Royal Liverpool University Hospital or at another hospital. Histologic examination was performed using formalin-fixed paraffin-embedded tissue. Sections through the tumor site were stained routinely with hematoxylin and eosin; special stains and immunohistochemistry using HMB-45 for melanocytes were used at the discretion of the pathologist. The case notes, histologic features, and computer database were reviewed. The information collated included patient and tumor characteristics on initial presentation and over the subsequent clinical course, reasons for endoresection, and reasons for enucleation. Records from other hospitals were used if necessary. Internal review board approval was not required.
Results Findings at Primary Endoresection Sixty-one endoresections were performed at Royal Liverpool University Hospital during the study period, all for choroidal mela-
noma. One patient was excluded because his endoresection was abandoned during surgery because of posterior scleral perforation, and the eye was enucleated as primary treatment. Twelve of these eyes subsequently were enucleated. Patient characteristics are listed in Table 1. In all but 2 patients, the tumor extended to within 1 disc diameter of the optic disc. Plaque radiotherapy (2 patients) and phototherapy (1 patient) had been given as adjuvant therapy at the time of endoresection (Table 2). An example of a patient who was offered endoresection is patient 6. He had a visual acuity of counting fingers in his other eye, and a choroidal tumor that involved 4 clock hours of the optic disc (Fig 1). The tumor measured 11.6 mm in its largest basal diameter and was 7.2 mm thick. It was believed that the risk of optic neuropathy with any form of radiotherapy was high, and enucleation was unacceptable to the patient because of his limited visual acuity in the other eye. Figure 2 shows the tumor recurrence in this patient, extending away from the surgical coloboma and around the temporal side of the optic disc. The reasons for enucleation were (1) local tumor recurrence detected by ophthalmoscopy (2 patients) or echography (1 patient); (2) opaque media preventing adequate ophthalmoscopy (4 patients); (3) blind and painful eye of uncertain cause that was enucleated at another hospital (1 patient); and (4) a combination of blind eye and limited fundus view (4 patients), which was the result of untreatable retinal detachment (3 patients) and endophthalmitis (1 patient; Table 2). In patients who had silicone oil in their eye when the decision was made to enucleate, echography also was inadequate. This included 2 patients with no fundus view and 2 patients with blind and painful eyes and a limited fundus view. We were unable to follow up 1 patient (patient 4) because her ophthalmologist took over her care. She was eventually referred back to us by another ophthalmologist, and we immediately performed enucleation because opaque media precluded adequate ophthalmoscopy. Histologic examination of the initial endoresection specimens revealed that the tumor cell types were spindle B (5 tumors), epithelioid (2 tumors), and mixed (4 tumors). Histologic examination results were not available for 1 case. Fragmentation of the specimen limited assessment of tumor necrosis, mitotic activity, vascular patterns, and lymphocytic infiltration; a delay in fixation,
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Ophthalmology Volume 111, Number 1, January 2004 Table 2. Reasons for and Timing of Enucleation Patient No.
Adjunctive Treatment at Endoresection
Reason for Enucleation*
Time to Enucleation (mos)
1 2 3
1 2 1
Nil Nil Plaque radiotherapy
15 7 57
4
1 and 3
Nil
63
5 6
1 and 2 4
21 25
7
1, 2, and 3
Nil Transpupillary thermotherapy, argon laser Plaque radiotherapy
8
1, 2, and 3
Nil
1
9
4
Nil
52
10
3 and 4
Nil
22
11
1 and 2
Nil
37
12
1 and 3
Nil
88
23
Recurrence Characteristics
Cell Type of Recurrence
Nil Nil Intrascleral, 6 mm diameter, 8 mm thick Adjacent to resection margin, extensive and diffuse throughout posterior segment Nil At optic disc, microscopic
Nil Nil Mixed
At optic disc, microscopic Adjacent to resection margin, microscopic At optic disc, 2 mm diameter, ⬍1 mm thick At optic disc, 6 mm diameter, ⬍1 mm thick Adjacent to resection margin, microscopic Nil
Epithelioid
Spindle
Nil Spindle
Mixed Mixed Mixed Spindle Nil
*Reasons for enucleation: (1) no or limited fundus view, (2) blind and in some cases painful eye, (3) silicone oil preventing echography, (4) clinical recurrence, either on ophthalmoscopy, echography, or both.
given that the specimen remained in the vitrectomy cassette during the operation, also tended to alter cellular morphologic features (Fig 3) when compared with enucleation (Fig 4, same patient).
Findings at Enucleation Residual tumor was present in 8 of the 12 eyes. This had been detected clinically in 3 eyes, either by ophthalmoscopy (2 eyes) or echography (1 eye). In 5 eyes, the tumor was not visible clinically because of opaque media (2 eyes), because of retinal detachment (2 eyes), or because of endophthalmitis (1 eye). Echography was inadequate because of silicone oil in 3 of these patients (Table 2). One of the patients with an inadequate fundus view had an intrascleral recurrence that would not have been visible ophthalmoscopically, and this patient has been the subject of a previous report.6 This was the only case of extrascleral extension in our series of tumors. The recurrent or persistent lesions tended to be of the same cell type as the endoresection specimen, with the exception of 1 mixed cell type tumor that had a spindle cell recurrence, and 1 of mixed cell type that had an epithelioid recurrence (Table 2). In all cases, the recurrent tumor was located at the edge of the site of the surgical resection or within this area. One recurred within the sclera and 1 in the retina immediately adjacent to the optic disc (Fig 4, patient 6). The other 6 recurred within the choroid adjacent to the resected area (Fig 5, patient 10). In the 1 patient who had been lost to follow-up, there was extensive diffuse infiltration of spindle cell tumor throughout the eye (Figs 6 – 8,
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patient 4). Two patients had recurrent tumors with thicknesses more than 2 mm; the other 8 were either microscopic or less than 1 mm thick (Table 2). Apart from tumor, all eyes with silicone oil tamponade also showed histologic features associated with silicone oil use. These features have been described previously.7 Patient 4 subsequently died of metastatic melanoma, the only one of the 12 enucleated patients in whom metastatic disease developed, and one of only 2 patients in the entire series of 61 patients to have metastatic disease. Seven of the 61 patients have died of unrelated causes.
Discussion Endoresection is a controversial procedure because of intuitive fears about inducing dissemination of malignant melanoma cells throughout the globe. Because of these concerns, we have performed endoresection only if other methods were considered unlikely to conserve a useful eye. Furthermore, we took appropriate measures to ensure that all patients were fully aware of the limited worldwide experience with this technique and the uncertain outcome. In view of the concerns about tumor seeding, the most important finding of this study was that in all patients enucleated, the recurrent tumor was located at the site of the original malignancy. One patient did have an extensive and diffuse tumor spread and seeding at the time of enucleation,
Hadden et al 䡠 Histopathology of Endoresection
Figure 1. Patient 6. Fundus photograph of the left eye. A pigmented choroidal tumor is visible inferior to and involving the optic disc over 4 clock hours.
but we believe these occurred because of delayed detection and treatment of tumor recurrence at the site of the original tumor. The creation of a retinal defect removes a natural barrier to tumor seeding in the presence of untreated residual disease. Other authors have expressed concern that tumor seeding to other parts of the eye may be a potential hazard after endoresection.8 We believe that the tumor spread in our case probably arose from untreated residual disease rather than tumor dispersion at the time of the initial surgery. Another important finding was that 5 of the tumor recurrences were discovered only on histologic examination, and this result substantiated our policy of recommending enucleation if there were any obstacles to ophthalmoscopic or echographic monitoring.
To our knowledge, this is the first histopathologic study of a series of eyes enucleated for complications arising from endoresection. As far as we are aware, this sample is derived from the largest series of endoresections reported to date. Another strength of this study is that there is a significant period of follow-up in most patients. The main weakness of this study is that we did not perform serial sections to exclude microscopic seedlings. Furthermore, some patients may yet experience local recurrence in the future, perhaps several decades after the original surgery. For these reasons, some small residual tumors may have been missed clinically or histologically. With regard to clinical recurrences, these patients are still under-
Figure 2. Patient 6. Fundus photograph of the left eye. An endoresection site is visible inferior to the disc, in the site of a previous melanoma. Recurrent tumor is visible adjacent to the temporal part of the optic disc (arrow). Image brightness and contrast have been enhanced to show better the recurrent tumor.
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Ophthalmology Volume 111, Number 1, January 2004
Figure 3. Patient 6. Cells in this choroidal melanoma endoresection fragment appear chiefly spindle. The morphologic features may be distorted by the delay in fixation and mechanical damage during endoresection. Figure 4 shows the same tumor after enucleation for comparison (stain, hematoxylin– eosin; original magnification, ⫻500). Figure 4. Patient 6. Recurrent choroidal melanoma (black arrow) has extended from the retina into the optic nerve head. This is the same tumor as in Figure 3, for comparison (stain, hematoxylin– eosin; original magnification, ⫻100). Figure 5. Patient 10. Recurrent choroidal melanoma (black arrow) is present in the choroid, adjacent to the laser scar (red arrow) at the edge of the surgical coloboma (stain, hematoxylin– eosin; original magnification, ⫻200). Figure 6. Patient 4. An extensive and diffuse recurrence of choroidal melanoma is visible throughout the posterior segment (stain, hematoxylin– eosin). The recurrence is located in the choroid (Fig 7) and is of spindle cell type (Fig 8). In this section, the retina is detached and hence not visible here. Figure 7. Patient 4. The melanoma is seen to lie within the choroid. The retinal pigment epithelium (arrow) and neuroretina (R) are marked for orientation purposes (stain, hematoxylin– eosin of another area to Fig 6; original magnification, ⫻200). Figure 8. Patient 4. The melanoma is seen to consist of malignant spindle-shaped cells (stain, hematoxylin– eosin; original magnification, ⫻800).
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Hadden et al 䡠 Histopathology of Endoresection going lifelong monitoring, and in due course any future recurrences will be reported in further publications. It is not possible to compare this histologic study with a similar series from another center because, as far as we know, no similar study has been performed. It would be interesting to compare these cases with eyes enucleated for local tumor recurrence after other forms of conservative treatment, particularly transpupillary thermotherapy. Diaz et al9 made 2 anecdotal reports in which residual viable tumor was located in the same area as the original tumor. Damato et al reported on residual and recurrent uveal melanoma after transscleral local resection according to the method of Foulds. They found that 24 patients had residual tumor and 57 delayed local recurrence, of a total of 310 patients.10 The sole best indicator of the risk of recurrent disease was proximity (within 1 disc diameter) of the melanoma to the optic disc.10 Four of our recurrences also occurred at this location. It is not the purpose of this study to report on the overall incidence of local tumor recurrence after endoresection. Review of our database suggests that to date there have been 3 patients with possible or definite local tumor recurrence treated by phototherapy, without enucleation (unpublished data). Of course, by definition we do not have data on rates of subclinical tumor persistence or recurrence in retained eyes. Neither do we have autopsy data on such eyes. As mentioned above, all local tumor recurrences occurred at the site of the primary melanoma, with 4 of these recurrent tumors located at the disc margin. These results suggest that the recurrences arose from lateral tumor extensions that were not visible clinically at the time of the endoresection. The main implication of this finding is that the resection should be performed with wide clearance margins and perhaps followed by adjunctive plaque radiotherapy. It should be possible to deliver such adjunctive radiotherapy without causing significant morbidity, first because of the small dose of radiation that needs to be delivered (i.e., 100 Gy to a depth of 2 mm), and second, because it should be possible to position the plaque away from the optic nerve. Such an approach would not sterilize tumor deposits at the disc margin. It is noteworthy that 4 of the 8 recurrent tumors were located in this area. It may be argued that tumors with significant disc involvement should be treated by primary enucleation rather than endoresection; however, 24 of the 61 patients showed this adverse feature, and in the large majority, recurrent disease so far has not developed. When considering all 61 patients undergoing endoresection, the mean basal tumor diameter was 8.9 mm with a mean thickness of 4.1 mm. Our sample is too small to make a statistically valid comment, but most patients with recurrent tumor seem to have had primary tumors that tended to be slightly larger than this (Table 1). We have tried to prevent local recurrence at the disc margin by administering vigorous diathermy and endolaser photocoagulation to this area. There is perhaps a role for further phototherapy being applied to this area in the postoperative period. We recommended enucleation in all eyes in which there was a limited fundus view; this was a primary factor in the decision to enucleate in 8 of the 12 patients. It should be
noted that this study includes all patients undergoing endoresection and therefore includes those treated during our learning phase. The most significant intraoperative complication that resulted in difficulty obtaining an adequate fundus view at a later date was the presence of an entry-site tear, with subsequent retinal detachment. The results and ocular complications of this surgery have been reported previously for this series of patients.5 As with any form of conservative therapy, we have always advocated prompt enucleation of any eyes that could not be examined adequately by ophthalmoscopy for the presence of local tumor recurrence. This conservative policy resulted in 4 recurrent tumors being detected at an early stage. One patient with a very extensive tumor (patient 4) had a very extensive tumor recurrence in an eye that was not monitored adequately because of opaque media and the presence of silicone oil. This patient had been discharged to her local ophthalmologist because she lived a great distance from our center. On the basis of this adverse experience, we continue to emphasize the need for early enucleation if proper surveillance is not possible. It is interesting that in 2 patients, the recurrent tumors were different histologically compared with the original lesion. This is probably the result either of sampling error or of morphologic distortion induced in the specimen during the endoresection procedure, although it is possible that transformation from one cell type to another occurred because of differential growth of different cell clones in the same tumor. A similar kind of transformation has been noted after local resection.11 Our indications for transretinal endoresection have changed during the course of this study. We originally started performing endoresection because of the morbidity caused by photocoagulation as well as the high incidence of optic neuropathy after proton beam radiotherapy. In the late 1990s, when there was initial enthusiasm about the results of TTT, we treated several patients with this technique instead of performing endoresection. However, we have seen several patients with local tumor recurrence after TTT. Shields et al reported a 22% recurrence at 3 years after TTT.4 At present, we are evaluating proton beam radiotherapy with a reduced safety margin at the optic disc, but it is too early to report on the efficacy of this treatment as compared with endoresection. In conclusion, all recurrences have occurred at the site of the primary tumor, and the one case of extensive seeding around the posterior segment probably occurred because of untreated marginal recurrence in the presence of an adjacent retinal defect. We continue to perform this procedure in a small number of patients when this seems to offer the best chance of conserving vision. These patients are being monitored carefully, and we hope to be able to continue to report our results in the future.
References 1. Egan KM, Seddon JM, Glynn RJ, et al. Epidemiological aspects of uveal melanoma. Surv Ophthalmol 1988;32:239 – 51.
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Ophthalmology Volume 111, Number 1, January 2004 2. Scotto J, Fraumeni JF Jr, Lee JA. Melanomas of the eye and other noncutaneous sites: epidemiologic aspects. J Natl Cancer Inst 1976;56:489 –91. 3. Diener-West M, Earle JD, Fine SL, et al, 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 – 82. 4. Shields CL, Shields JA, Perez N, et al. Primary transpupillary thermotherapy for small choroidal melanoma in 256 consecutive cases: outcomes and limitations. Ophthalmology 2002; 109:225–34. 5. Damato B, Groenewald C, McGalliard J, Wong D. Endoresection of choroidal melanoma. Br J Ophthalmol 1998;82:213– 8. 6. Damato B, Wong D, Green FD, Mackenzie JM. Intrascleral recurrence of uveal melanoma after transretinal “endoresection” [letter]. Br J Ophthalmol 2001;85:114 –5.
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7. Leaver PK, Grey RH, Garner A. Silicone oil injection in the treatment of massive preretinal retraction. II. Late complications in 93 eyes. Br J Ophthalmol 1979;63:361–7. 8. Bornfeld N, Talies S, Anastassiou G, et al. Endoresektion maligner Melanome der Uvea nach pra¨ operativer stereotaktischer Einzeldosis-Konvergenzbestrahlung mit dem LeskellGamma-knife. Ophthalmologe 2002;99:338 – 44. 9. Diaz CE, Capone A Jr, Grossniklaus HE. Clinicopathologic findings in recurrent choroidal melanoma after transpupillary thermotherapy. Ophthalmology 1998;105:1419 –24. 10. Damato BE, Paul J, Foulds WS. Risk factors for residual and recurrent uveal melanoma after trans-scleral local resection. Br J Ophthalmol 1996;80:102– 8. 11. Bechrakis NE, Sehu KW, Lee WR, et al. Transformation of cell type in uveal melanomas: a quantitative histologic analysis. Arch Ophthalmol 2000;118:1406 –12.
Uveal melanoma, although a relatively rare disease, is the most common primary intraocular malignancy, with an incidence of 6 to 7 per 1 million per year.1,2 Of these tumors, 80% are choroidal. The treatment of choroidal melanoma may be either radical (i.e., enucleation) or aimed at conserving the eye with as much vision as possible (i.e., conservative treatment). Conservative treatment of choroidal melanoma includes radiotherapy, phototherapy, and local resection. Radiotherapy has been shown to be as effective as enucleation in Originally received: August 1, 2002. Accepted: May 5, 2003. Manuscript no. 220528. From the Liverpool Ocular Oncology Centre, St. Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom. Correspondence to Dr Peter W. Hadden, Liverpool Ocular Oncology Centre, St. Paul’s Eye Unit, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, United Kingdom. E-mail: peterandandy@ hotmail.com. Reprint requests to Bertil E. Damato, Liverpool Ocular Oncology Centre, St. Paul’s Eye Unit, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, United Kingdom. E-mail: Bertil.Damato@ BTInternet.com.
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© 2004 by the American Academy of Ophthalmology Published by Elsevier Inc.
preventing mortality from medium-sized choroidal melanomas3 and is the most common first-line treatment. It usually is delivered with ruthenium or iodine plaque brachytherapy, but also may be given by charged particles or in the form of stereotactic radiotherapy. Photocoagulation largely has been superseded by transpupillary thermotherapy (TTT). Because TTT is a relatively recent innovation, long-term results are not yet available.4 Endoresection, described in detail by Damato et al,5 was developed in an attempt to overcome the limitations of radiotherapy options for juxtapapillary lesions. It is used most often in cases in which a choroidal melanoma extends within 1 disc diameter of the optic nerve, or in cases of recurrent tumor after other forms of treatment. It is not at present considered (1) for tumors that involve more than one third of the disc margin, because the prognosis for vision in such cases is limited, (2) for diffuse tumors, or (3) for those with a basal diameter more than 10 to 11 mm. If there is any question regarding the adequacy of tumor resection, adjunctive plaque brachytherapy may be used. Transpupillary thermotherapy also can be administered, either before or after surgery. ISSN 0161-6420/04/$–see front matter doi:10.1016/j.ophtha.2003.05.007
Hadden et al 䡠 Histopathology of Endoresection Table 1. Clinical Features at Endoresection
Patient No. 1 2 3 4 5 6 7 8 9 10 11 12
Age (yrs)
Gender
Eye
Location with Respect to Optic Disc
67 81 40 25 56 51 76 60 61 44 46 45
F F M F F M M F F M M F
R R R L L L L L L R R L
Inferior Inferior Inferior Inferonasal Nasal Inferonasal Superonasal Nasal Temporal Inferonasal Superior Temporal
Largest Basal Diameter 11.0 mm 5.2 mm 12.0 mm 9.0 mm 6.1 mm 11.6 mm 8.8 mm 10.0 mm 5.0 mm 8.0 mm 9.9 mm 5.2 mm
Thickness 6.5 1.9 4.8 4.0 3.0 7.2 5.0 2.0 4.0 2.4 6.7 2.3
mm mm mm mm mm mm mm mm mm mm mm mm
Distance to Disc
Amount of Disc Margin Involved*
Tumor Cell Type
0 mm ⬍1 DD ⬍1 DD Macula 0 mm 0 mm 0 mm ⬍1 DD 0 mm ⬍1 DD Equator 0 mm
3 Nil Nil Nil 2 1 1 Nil 4 Nil Nil 1
Spindle Spindle† Mixed Unknown‡ Spindle Mixed Epithelioid Mixed Epithelioid Spindle Mixed Spindle
F ⫽ female; L ⫽ left; M ⫽ male; R ⫽ right. *In clock hours. † Only one small fragment of tumor, specimen too small to confirm malignancy absolutely by cytologic or histologic criteria. ‡ No histologic results available.
Endoresection of choroidal melanoma is controversial because of fears that piecemeal tumor removal would result in tumor seeding around the eye; therefore, it is performed only in a few centers, where it is reserved for patients in whom preservation of vision is important in the tumoraffected eye. The aim of this study was to demonstrate the histopathologic features of eyes enucleated after endoresection to determine the frequency of subclinical, microscopic, residual tumor both at the site of the coloboma and in other parts of the eye.
Materials and Methods All patients undergoing endoresection at the Royal Liverpool University Hospital between January 1, 1993 and February 28, 2002 were identified retrospectively using a computer database. The technique of endoresection used in this study has been described previously.5 Eyes were enucleated at the Royal Liverpool University Hospital or at another hospital. Histologic examination was performed using formalin-fixed paraffin-embedded tissue. Sections through the tumor site were stained routinely with hematoxylin and eosin; special stains and immunohistochemistry using HMB-45 for melanocytes were used at the discretion of the pathologist. The case notes, histologic features, and computer database were reviewed. The information collated included patient and tumor characteristics on initial presentation and over the subsequent clinical course, reasons for endoresection, and reasons for enucleation. Records from other hospitals were used if necessary. Internal review board approval was not required.
Results Findings at Primary Endoresection Sixty-one endoresections were performed at Royal Liverpool University Hospital during the study period, all for choroidal mela-
noma. One patient was excluded because his endoresection was abandoned during surgery because of posterior scleral perforation, and the eye was enucleated as primary treatment. Twelve of these eyes subsequently were enucleated. Patient characteristics are listed in Table 1. In all but 2 patients, the tumor extended to within 1 disc diameter of the optic disc. Plaque radiotherapy (2 patients) and phototherapy (1 patient) had been given as adjuvant therapy at the time of endoresection (Table 2). An example of a patient who was offered endoresection is patient 6. He had a visual acuity of counting fingers in his other eye, and a choroidal tumor that involved 4 clock hours of the optic disc (Fig 1). The tumor measured 11.6 mm in its largest basal diameter and was 7.2 mm thick. It was believed that the risk of optic neuropathy with any form of radiotherapy was high, and enucleation was unacceptable to the patient because of his limited visual acuity in the other eye. Figure 2 shows the tumor recurrence in this patient, extending away from the surgical coloboma and around the temporal side of the optic disc. The reasons for enucleation were (1) local tumor recurrence detected by ophthalmoscopy (2 patients) or echography (1 patient); (2) opaque media preventing adequate ophthalmoscopy (4 patients); (3) blind and painful eye of uncertain cause that was enucleated at another hospital (1 patient); and (4) a combination of blind eye and limited fundus view (4 patients), which was the result of untreatable retinal detachment (3 patients) and endophthalmitis (1 patient; Table 2). In patients who had silicone oil in their eye when the decision was made to enucleate, echography also was inadequate. This included 2 patients with no fundus view and 2 patients with blind and painful eyes and a limited fundus view. We were unable to follow up 1 patient (patient 4) because her ophthalmologist took over her care. She was eventually referred back to us by another ophthalmologist, and we immediately performed enucleation because opaque media precluded adequate ophthalmoscopy. Histologic examination of the initial endoresection specimens revealed that the tumor cell types were spindle B (5 tumors), epithelioid (2 tumors), and mixed (4 tumors). Histologic examination results were not available for 1 case. Fragmentation of the specimen limited assessment of tumor necrosis, mitotic activity, vascular patterns, and lymphocytic infiltration; a delay in fixation,
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Ophthalmology Volume 111, Number 1, January 2004 Table 2. Reasons for and Timing of Enucleation Patient No.
Adjunctive Treatment at Endoresection
Reason for Enucleation*
Time to Enucleation (mos)
1 2 3
1 2 1
Nil Nil Plaque radiotherapy
15 7 57
4
1 and 3
Nil
63
5 6
1 and 2 4
21 25
7
1, 2, and 3
Nil Transpupillary thermotherapy, argon laser Plaque radiotherapy
8
1, 2, and 3
Nil
1
9
4
Nil
52
10
3 and 4
Nil
22
11
1 and 2
Nil
37
12
1 and 3
Nil
88
23
Recurrence Characteristics
Cell Type of Recurrence
Nil Nil Intrascleral, 6 mm diameter, 8 mm thick Adjacent to resection margin, extensive and diffuse throughout posterior segment Nil At optic disc, microscopic
Nil Nil Mixed
At optic disc, microscopic Adjacent to resection margin, microscopic At optic disc, 2 mm diameter, ⬍1 mm thick At optic disc, 6 mm diameter, ⬍1 mm thick Adjacent to resection margin, microscopic Nil
Epithelioid
Spindle
Nil Spindle
Mixed Mixed Mixed Spindle Nil
*Reasons for enucleation: (1) no or limited fundus view, (2) blind and in some cases painful eye, (3) silicone oil preventing echography, (4) clinical recurrence, either on ophthalmoscopy, echography, or both.
given that the specimen remained in the vitrectomy cassette during the operation, also tended to alter cellular morphologic features (Fig 3) when compared with enucleation (Fig 4, same patient).
Findings at Enucleation Residual tumor was present in 8 of the 12 eyes. This had been detected clinically in 3 eyes, either by ophthalmoscopy (2 eyes) or echography (1 eye). In 5 eyes, the tumor was not visible clinically because of opaque media (2 eyes), because of retinal detachment (2 eyes), or because of endophthalmitis (1 eye). Echography was inadequate because of silicone oil in 3 of these patients (Table 2). One of the patients with an inadequate fundus view had an intrascleral recurrence that would not have been visible ophthalmoscopically, and this patient has been the subject of a previous report.6 This was the only case of extrascleral extension in our series of tumors. The recurrent or persistent lesions tended to be of the same cell type as the endoresection specimen, with the exception of 1 mixed cell type tumor that had a spindle cell recurrence, and 1 of mixed cell type that had an epithelioid recurrence (Table 2). In all cases, the recurrent tumor was located at the edge of the site of the surgical resection or within this area. One recurred within the sclera and 1 in the retina immediately adjacent to the optic disc (Fig 4, patient 6). The other 6 recurred within the choroid adjacent to the resected area (Fig 5, patient 10). In the 1 patient who had been lost to follow-up, there was extensive diffuse infiltration of spindle cell tumor throughout the eye (Figs 6 – 8,
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patient 4). Two patients had recurrent tumors with thicknesses more than 2 mm; the other 8 were either microscopic or less than 1 mm thick (Table 2). Apart from tumor, all eyes with silicone oil tamponade also showed histologic features associated with silicone oil use. These features have been described previously.7 Patient 4 subsequently died of metastatic melanoma, the only one of the 12 enucleated patients in whom metastatic disease developed, and one of only 2 patients in the entire series of 61 patients to have metastatic disease. Seven of the 61 patients have died of unrelated causes.
Discussion Endoresection is a controversial procedure because of intuitive fears about inducing dissemination of malignant melanoma cells throughout the globe. Because of these concerns, we have performed endoresection only if other methods were considered unlikely to conserve a useful eye. Furthermore, we took appropriate measures to ensure that all patients were fully aware of the limited worldwide experience with this technique and the uncertain outcome. In view of the concerns about tumor seeding, the most important finding of this study was that in all patients enucleated, the recurrent tumor was located at the site of the original malignancy. One patient did have an extensive and diffuse tumor spread and seeding at the time of enucleation,
Hadden et al 䡠 Histopathology of Endoresection
Figure 1. Patient 6. Fundus photograph of the left eye. A pigmented choroidal tumor is visible inferior to and involving the optic disc over 4 clock hours.
but we believe these occurred because of delayed detection and treatment of tumor recurrence at the site of the original tumor. The creation of a retinal defect removes a natural barrier to tumor seeding in the presence of untreated residual disease. Other authors have expressed concern that tumor seeding to other parts of the eye may be a potential hazard after endoresection.8 We believe that the tumor spread in our case probably arose from untreated residual disease rather than tumor dispersion at the time of the initial surgery. Another important finding was that 5 of the tumor recurrences were discovered only on histologic examination, and this result substantiated our policy of recommending enucleation if there were any obstacles to ophthalmoscopic or echographic monitoring.
To our knowledge, this is the first histopathologic study of a series of eyes enucleated for complications arising from endoresection. As far as we are aware, this sample is derived from the largest series of endoresections reported to date. Another strength of this study is that there is a significant period of follow-up in most patients. The main weakness of this study is that we did not perform serial sections to exclude microscopic seedlings. Furthermore, some patients may yet experience local recurrence in the future, perhaps several decades after the original surgery. For these reasons, some small residual tumors may have been missed clinically or histologically. With regard to clinical recurrences, these patients are still under-
Figure 2. Patient 6. Fundus photograph of the left eye. An endoresection site is visible inferior to the disc, in the site of a previous melanoma. Recurrent tumor is visible adjacent to the temporal part of the optic disc (arrow). Image brightness and contrast have been enhanced to show better the recurrent tumor.
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Figure 3. Patient 6. Cells in this choroidal melanoma endoresection fragment appear chiefly spindle. The morphologic features may be distorted by the delay in fixation and mechanical damage during endoresection. Figure 4 shows the same tumor after enucleation for comparison (stain, hematoxylin– eosin; original magnification, ⫻500). Figure 4. Patient 6. Recurrent choroidal melanoma (black arrow) has extended from the retina into the optic nerve head. This is the same tumor as in Figure 3, for comparison (stain, hematoxylin– eosin; original magnification, ⫻100). Figure 5. Patient 10. Recurrent choroidal melanoma (black arrow) is present in the choroid, adjacent to the laser scar (red arrow) at the edge of the surgical coloboma (stain, hematoxylin– eosin; original magnification, ⫻200). Figure 6. Patient 4. An extensive and diffuse recurrence of choroidal melanoma is visible throughout the posterior segment (stain, hematoxylin– eosin). The recurrence is located in the choroid (Fig 7) and is of spindle cell type (Fig 8). In this section, the retina is detached and hence not visible here. Figure 7. Patient 4. The melanoma is seen to lie within the choroid. The retinal pigment epithelium (arrow) and neuroretina (R) are marked for orientation purposes (stain, hematoxylin– eosin of another area to Fig 6; original magnification, ⫻200). Figure 8. Patient 4. The melanoma is seen to consist of malignant spindle-shaped cells (stain, hematoxylin– eosin; original magnification, ⫻800).
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Hadden et al 䡠 Histopathology of Endoresection going lifelong monitoring, and in due course any future recurrences will be reported in further publications. It is not possible to compare this histologic study with a similar series from another center because, as far as we know, no similar study has been performed. It would be interesting to compare these cases with eyes enucleated for local tumor recurrence after other forms of conservative treatment, particularly transpupillary thermotherapy. Diaz et al9 made 2 anecdotal reports in which residual viable tumor was located in the same area as the original tumor. Damato et al reported on residual and recurrent uveal melanoma after transscleral local resection according to the method of Foulds. They found that 24 patients had residual tumor and 57 delayed local recurrence, of a total of 310 patients.10 The sole best indicator of the risk of recurrent disease was proximity (within 1 disc diameter) of the melanoma to the optic disc.10 Four of our recurrences also occurred at this location. It is not the purpose of this study to report on the overall incidence of local tumor recurrence after endoresection. Review of our database suggests that to date there have been 3 patients with possible or definite local tumor recurrence treated by phototherapy, without enucleation (unpublished data). Of course, by definition we do not have data on rates of subclinical tumor persistence or recurrence in retained eyes. Neither do we have autopsy data on such eyes. As mentioned above, all local tumor recurrences occurred at the site of the primary melanoma, with 4 of these recurrent tumors located at the disc margin. These results suggest that the recurrences arose from lateral tumor extensions that were not visible clinically at the time of the endoresection. The main implication of this finding is that the resection should be performed with wide clearance margins and perhaps followed by adjunctive plaque radiotherapy. It should be possible to deliver such adjunctive radiotherapy without causing significant morbidity, first because of the small dose of radiation that needs to be delivered (i.e., 100 Gy to a depth of 2 mm), and second, because it should be possible to position the plaque away from the optic nerve. Such an approach would not sterilize tumor deposits at the disc margin. It is noteworthy that 4 of the 8 recurrent tumors were located in this area. It may be argued that tumors with significant disc involvement should be treated by primary enucleation rather than endoresection; however, 24 of the 61 patients showed this adverse feature, and in the large majority, recurrent disease so far has not developed. When considering all 61 patients undergoing endoresection, the mean basal tumor diameter was 8.9 mm with a mean thickness of 4.1 mm. Our sample is too small to make a statistically valid comment, but most patients with recurrent tumor seem to have had primary tumors that tended to be slightly larger than this (Table 1). We have tried to prevent local recurrence at the disc margin by administering vigorous diathermy and endolaser photocoagulation to this area. There is perhaps a role for further phototherapy being applied to this area in the postoperative period. We recommended enucleation in all eyes in which there was a limited fundus view; this was a primary factor in the decision to enucleate in 8 of the 12 patients. It should be
noted that this study includes all patients undergoing endoresection and therefore includes those treated during our learning phase. The most significant intraoperative complication that resulted in difficulty obtaining an adequate fundus view at a later date was the presence of an entry-site tear, with subsequent retinal detachment. The results and ocular complications of this surgery have been reported previously for this series of patients.5 As with any form of conservative therapy, we have always advocated prompt enucleation of any eyes that could not be examined adequately by ophthalmoscopy for the presence of local tumor recurrence. This conservative policy resulted in 4 recurrent tumors being detected at an early stage. One patient with a very extensive tumor (patient 4) had a very extensive tumor recurrence in an eye that was not monitored adequately because of opaque media and the presence of silicone oil. This patient had been discharged to her local ophthalmologist because she lived a great distance from our center. On the basis of this adverse experience, we continue to emphasize the need for early enucleation if proper surveillance is not possible. It is interesting that in 2 patients, the recurrent tumors were different histologically compared with the original lesion. This is probably the result either of sampling error or of morphologic distortion induced in the specimen during the endoresection procedure, although it is possible that transformation from one cell type to another occurred because of differential growth of different cell clones in the same tumor. A similar kind of transformation has been noted after local resection.11 Our indications for transretinal endoresection have changed during the course of this study. We originally started performing endoresection because of the morbidity caused by photocoagulation as well as the high incidence of optic neuropathy after proton beam radiotherapy. In the late 1990s, when there was initial enthusiasm about the results of TTT, we treated several patients with this technique instead of performing endoresection. However, we have seen several patients with local tumor recurrence after TTT. Shields et al reported a 22% recurrence at 3 years after TTT.4 At present, we are evaluating proton beam radiotherapy with a reduced safety margin at the optic disc, but it is too early to report on the efficacy of this treatment as compared with endoresection. In conclusion, all recurrences have occurred at the site of the primary tumor, and the one case of extensive seeding around the posterior segment probably occurred because of untreated marginal recurrence in the presence of an adjacent retinal defect. We continue to perform this procedure in a small number of patients when this seems to offer the best chance of conserving vision. These patients are being monitored carefully, and we hope to be able to continue to report our results in the future.
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Ophthalmology Volume 111, Number 1, January 2004 2. Scotto J, Fraumeni JF Jr, Lee JA. Melanomas of the eye and other noncutaneous sites: epidemiologic aspects. J Natl Cancer Inst 1976;56:489 –91. 3. Diener-West M, Earle JD, Fine SL, et al, 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 – 82. 4. Shields CL, Shields JA, Perez N, et al. Primary transpupillary thermotherapy for small choroidal melanoma in 256 consecutive cases: outcomes and limitations. Ophthalmology 2002; 109:225–34. 5. Damato B, Groenewald C, McGalliard J, Wong D. Endoresection of choroidal melanoma. Br J Ophthalmol 1998;82:213– 8. 6. Damato B, Wong D, Green FD, Mackenzie JM. Intrascleral recurrence of uveal melanoma after transretinal “endoresection” [letter]. Br J Ophthalmol 2001;85:114 –5.
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7. Leaver PK, Grey RH, Garner A. Silicone oil injection in the treatment of massive preretinal retraction. II. Late complications in 93 eyes. Br J Ophthalmol 1979;63:361–7. 8. Bornfeld N, Talies S, Anastassiou G, et al. Endoresektion maligner Melanome der Uvea nach pra¨ operativer stereotaktischer Einzeldosis-Konvergenzbestrahlung mit dem LeskellGamma-knife. Ophthalmologe 2002;99:338 – 44. 9. Diaz CE, Capone A Jr, Grossniklaus HE. Clinicopathologic findings in recurrent choroidal melanoma after transpupillary thermotherapy. Ophthalmology 1998;105:1419 –24. 10. Damato BE, Paul J, Foulds WS. Risk factors for residual and recurrent uveal melanoma after trans-scleral local resection. Br J Ophthalmol 1996;80:102– 8. 11. Bechrakis NE, Sehu KW, Lee WR, et al. Transformation of cell type in uveal melanomas: a quantitative histologic analysis. Arch Ophthalmol 2000;118:1406 –12.