Germline retinoblastoma results from a somatic mutation involving loss or inactivation of the tumor suppressor gene located at 13q14.1 Absence of gene activity predisposes to retinoblastoma and other tumor development.1,2 The introduction of chemotherapy protocols with focal consolidation therapy has enhanced our ability to treat germline retinoblastoma while salvaging many eyes that would have been lost previously.3- 8 A secondary benefit has been that we are now preserving eyes with useful vision. However, because of the aggressive, multimodal therapy involved, patients often develop intraocular complications. We evaluated a group of patients who had undergone enucleation for retinoblastoma in one eye with salvage of the other eye and who had maintained tumor quiescence for a period of 12 months or longer in that eye. Our purpose was to determine how these patients fared following intraocular surgery of the salvaged eye.
We performed a retrospective review of all germline retinoblastoma cases from January 1, 1985, until December 31, 2000, to identify all patients who had undergone unilateral enucleation with salvage of the other eye. Cases were drawn from the records of the University of Tennessee, Memphis, Department of Ophthalmology, Memphis; the records of the Ophthalmic Oncology Service at St Jude Children’s Research Hospital, Memphis; and the private records of Retina Associates of Florida, Tampa. Cases were enrolled only if the salvaged eye achieved a 12-month period of tumor quiescence and then subsequently underwent intraocular surgery for non–tumor-control reasons. Tumor quiescence was defined as lack of documented tumor growth, lack of vitreous or subretinal seeding, lack of anterior chamber seeding, and lack of metastases. Eligible intraocular surgery included cataract extraction, barrier laser for retinal break, scleral buckle procedure, pars plana vitrectomy, and Nd:YAG laser capsulotomy. Original treatment of the retinoblastoma was recorded, as was the Reese-Ellsworth classification. The 3 primary outcomes were tumor activity, visual acuity, and development of complications. Tumor activity was classified as quiescent, recurrent, and extraocular. Tumor recurrence included documented tumor growth or reactivation of the retinoblastoma in the eye (new vitreous seeding, new subretinal seeding, anterior chamber seeding). Extraocular tumor activity included extraocular extension, orbital involvement, and distant metastases. Visual acuity was assessed by Snellen acuity under best-corrected conditions. Nontumor complications were defined as retinal detachment (serous, rhegmatogenous, or tractional), cataract, vitreous hemorrhage, hypotony, elevated intraocular pressure, development of posterior capsular opacification, and epiretinal membrane formation. If the salvaged eye was enucleated, appropriate histopathologic analysis was performed.
We identified 110 patients who were treated for retinoblastoma from January 1, 1985, to December 31, 2000. Six cases (5 girls and 1 boy) met the inclusion criteria and form the basis of this report. The average patient age at the time of diagnosis was 9.5 months (median, 8 months; range, 5-21 months). In 3 cases, the left eye was enucleated and in 3 cases, the right eye. The Reese-Ellsworth classification was type V for 3 eyes originally enucleated (Table 1, cases 4-6); for the fellow eyes, the classification was group IIB for 1 and group IVB for 2 (Table 1). The Reese-Ellsworth classification was not known for the patients in cases 1 through 3 because they were treated elsewhere initially. Fellow eye treatment included external beam radiotherapy in all 6 patients (Table 1). In 2 cases the patients underwent simultaneous chemotherapy and in 2 cases plaque brachytherapy labeled with radioactive iodine I 125 was subsequently (Table 1) used.
The average time to first surgery was 85.3 months (median, 85.5 months; range, 12-172 months). The indication for intraocular surgery was cataract in 4 patients and rhegmatogenous retinal detachment in 2 patients. A median of 2.5 additional surgeries (range, 0-5) per eye were needed. The average length of follow-up was 163.7 months (median, 156 months; range, 60-339 months).
Three of the 6 patients demonstrated tumor activity following intraocular surgery (cases 4-6). Two patients (cases 5 and 6) had undergone primary repair of rhegmatogenous retinal detachments while 1 patient (case 4) had undergone cataract surgery (Figure 1 and Figure 2). All 3 cases had pseudohypopyon an average of 13.3 months (median, 10 months; range, 4-26 months) following intraocular surgery. Case 4 underwent enucleation immediately for advanced anterior chamber seeding; case 5 was treated with systemic (cyclophosphamide, doxorubicin, and carboplatin) and intravitreal (carboplatin and etoposide) chemotherapy, followed by enucleation; and case 6 underwent 8 cycles of carboplatin and vincristine followed by enucleation. No case demonstrated extraocular extension, orbital involvement, or distant metastases. Histopathologic features are summarized in Table 2. One eye had scleral penetration through an emissary vessel and 2 eyes had involvement of the Schlemm canal.
Active tumor is visible behind the iris in the superonasal quadrant following cataract surgery (case 4).
Retinoblastoma seeds are present in the anterior chamber. The patient underwent subsequent enucleation (case 4).
Three patients had bilateral enucleation and had no vision (Table 1). One patient had a Snellen acuity of 20/30, 1 had counting fingers visual acuity, and 1 had hand motions visual acuity.
Rhegmatogenous retinal detachment was the most frequent nontumor activity complication following intraocular surgery, occurring a total of 4 times in 3 patients without obvious proliferative vitreoretinopathy. Patient 1 developed a rhegmatogenous retinal detachment that was repaired and subsequently redetached, patient 3 developed a retinal detachment following cataract extraction, and patient 5 developed a sequential retinal detachment following primary repair. One patient developed a tractional retinal detachment (Table 3). Vitreous hemorrhage occurred in 2 cases.
Current treatment regimens allow for salvage of the contralateral globe and visual function in patients with retinoblastoma.3- 8 However, as the posttreatment interval increases, we are now being confronted with the long-term complications of these regimens, including late retinal detachment and cataract. The risks and benefits of intraocular surgery to treat these complications have only begun to be defined. In our study, the rate of complications following intraocular surgery was high, with a total of 10 ocular complications and 3 tumor activations in 6 patients. The leading indication for surgery was cataract (n = 4) followed by rhegmatogenous retinal detachment (n = 2). The leading complication following intraocular surgery was rhegmatogenous retinal detachment (n = 4, in 3 patients). In 3 patients, the retinoblastoma reactivated following intraocular surgery after at least 12 months of tumor quiescence. In 2 of these patients, the indication for surgery was rhegmatogenous retinal detachment and in 1 case, cataract removal. All 3 of these patients had anterior chamber pseudohypopyon, underwent enucleation, and were treated with adjuvant systemic chemotherapy. Despite involvement of an emissary vessel in 1 case and Schlemm canal in 2 cases (1 with the emissary vessel) on histopathologic specimens from the enucleated eyes, there were no cases of macroscopic extraocular extension or metastasis.
The high number of rhegmatogenous retinal detachments is not surprising in that these eyes were subjected to numerous treatments with laser photocoagulation, cryotherapy, and transpupillary thermotherapy. It is likely that the normal vitreoretinal interface was disturbed by both the original treatment and subsequent surgery, resulting in thinning of the retina and atrophic breaks in the retina. While all retinas were eventually reattached, no definite retinal break was identified in any eye with rhegmatogenous retinal detachment.
Other studies have also reported rhegmatogenous retinal detachment following retinoblastoma treatment; although the retina was successfully reattached in many patients in these studies, other attempts at reattachment were unsuccessful and were followed by adverse sequelae in some cases. Madreperla and colleagues9 identified retinal breaks in 2 of 4 cases of late rhegmatogenous retinal detachment after successful treatment of retinoblastoma. Using vitreoretinal surgical techniques, they achieved successful reattachment in 3 cases without tumor reactivation.9 Similarly, Baumal and coworkers10 reported on 9 eyes in 9 patients with rhegmatogenous retinal detachment after treatment for retinoblastoma and were only able to definitively identify a break or dialysis in 5. In 4 eyes, the atrophic hole was located either in or near an area of cryotherapy or laser photocoagulation.10 Final anatomic reattachment was achieved in 5 of 8 eyes that underwent repair.10 Three of those were enucleated when tumor reactivation occurred.10 They advise a cautious approach to the repair of rhegmatogenous retinal detachments following successful treatment of retinoblastoma.10 Their study is similar to ours in that most patients (8 of 9) had bilateral disease.10 However, 7 of 8 patients with known history had their last tumor treatment within 36 weeks or less time10 compared with our study patients whose tumors had been quiescent for an average of 85.3 months.
Honavar and colleagues11 also addressed the issue of rhegmatogenous retinal detachment following treatment of retinoblastoma. They reported 8 patients who underwent scleral buckle procedure an average of 14 months after treatment for retinoblastoma. They achieved retinal reattachment in 6 cases. Retinoblastoma recurred in 5 cases, requiring enucleation in 4, and metastasized in 1. They advised that retinal-detachment repair should be delayed until 6 to 12 months after completion of retinoblastoma therapy. The study by Honavar and colleagues11 is the largest to date regarding the need for surgical intervention following retinoblastoma therapy. In their series of 45 patients, the median time to surgical intervention was 18 months after retinoblastoma therapy. Sequelae of surgical intervention included retinoblastoma recurrence in 14 (31%), enucleation in 16 (36%), and metastasis in 3 (7%). These outcomes were more likely to occur following scleral buckle procedure or pars plana vitrectomy. Sixteen patients achieved a final visual acuity greater than 20/200. This series differs from ours because it includes both germline and sporadic retinoblastoma cases and a shorter tumor-free interval.
Not all studies reported negative sequelae from intraocular surgery following treatment of retinoblastoma. A study by Portellos and Buckley12 reported results on 11 eyes in 8 patients who successfully underwent cataract extraction and intraocular lens implantation following treatment of retinoblastoma. The study included 4 patients with bilateral disease and 4 patients with unilateral disease. Nine eyes underwent primary and 2 underwent secondary intraocular lens implantation. The mean time from conclusion of external beam radiotherapy to cataract extraction was approximately 55 months (4.6 years). No eye developed tumor recurrence, extraocular spread, retinal detachment, or radiation retinopathy in this cohort. This study represents the second longest quiescent interval between tumor treatment and intraocular surgery, and it seems to indicate that cataract surgery is relatively safe.
In our study, cataract was the indication for surgery in 4 patients, with 1 patient developing tumor reactivation and undergoing enucleation. Two of 2 eyes undergoing primary intervention for rhegmatogenous retinal detachment with vitrectomy reactivated and underwent enucleation. Interestingly, the 2 eyes that developed rhegmatogenous retinal detachment following cataract surgery and underwent repair with vitrectomy did not have tumor reactivation.
In reviewing the data from our study and the previous reports,9- 11 we are left to conclude that development of rhegmatogenous retinal detachment is an ominous sign for both visual acuity and eye salvage. It is possible that development of rhegmatogenous retinal detachment may herald occult reactivation of the retinoblastoma. In this instance, tumor reactivation could place mechanical stress upon the retina, resulting in stretching of an already damaged tissue and allowing microscopic breaks to form and subsensory fluid to accumulate. Likewise, it is possible that surgical repair of retinal detachment reactivates dormant or incompletely eradicated tumor cells with an infusion of nutrients into the vitreous cavity.
In this case series of aggressive germline retinoblastoma where one eye was originally enucleated and the second eye noted to have no tumor activity for a median of 85.5 months, tumor reactivation occurred in 3 of 6 cases following primary repair of rhegmatogenous retinal detachment with vitrectomy. Our experience is similar to that of earlier studies with less aggressive tumors and shorter tumor-quiescence intervals. Additionally, cataract surgery resulted in tumor reactivation in 1 of 4 cases. The rate of postsurgical complications was high, particularly the development of rhegmatogenous retinal detachment. No case of extraocular tumor spread or metastasis was noted. We recommend that surgical intervention in patients with these types of germline retinoblastoma be undertaken with due consideration for the risk of tumor reactivation and enucleation, even after lengthy tumor-quiescence intervals.
Correspondence: Dr Wilson, Department of Ophthalmology, University of Tennessee Health Science Center, D-228, 956 Court Ave, Memphis, TN 38163 (firstname.lastname@example.org).
Financial Disclosure: None.
Moshfeghi DM, Wilson MW, Grizzard S, Haik BG. Intraocular Surgery After Treatment of Germline Retinoblastoma. Arch Ophthalmol. 2005;123(7):1008-1012. doi:10.1001/archopht.123.7.1008