Post-laminar optic nerve invasion in the presence of scleral invasion: Case for intensive adjuvant treatment in retinoblastoma

Dear Editor, Retinoblastoma is the most common intraocular malignancy of childhood. Depending upon the grouping (ICRB) and staging (IRSS) of retinoblastoma, various treatment modalities are employed to tackle this index tumor. Intraocular retinoblastoma stage 0 is managed with focal therapies, intra-arterial chemotherapy, intravenous chemotherapy, and stage 1 with enucleation. Extraocular tumors (Stage 2, Stage 3, Stage 4) are managed with enucleation/exenteration, intravenous chemotherapy, and EBRT (external beam radiotherapy). Although there is considerable variability in what constitutes high-risk histopathology (HRH) in an enucleated eye (stage 1), post-laminar optic nerve invasion (PLONI), optic nerve cut end involvement, massive choroidal invasion (>3 mm), scleral involvement, extrascleral involvement, and ciliary body invasion are well recognized as high-risk features for metastasis by most ocular oncologists. Accordingly, at most centers, adjuvant chemotherapy (at least six cycles) is provided after enucleation in cases of intraocular tumors, if any of these high-risk features are found on histopathology of the enucleated eye.[1] In case of optic nerve cut end invasion or extrascleral extension (microscopic residual disease), twelve cycles of chemotherapy plus EBRT are advised as per the current consensus. Scleral invasion presents a murky gray area where clinical opinions vary with regard to optimal adjuvant treatment. While some authors advocate radiotherapy, others advocate standard or a more aggressive chemotherapy only.[2] EBRT has numerous side effects with significant impact on cosmesis and increased risk of secondary tumors in cases with germline mutations. The occurrence of scleral invasion alone is infrequent as reported in studies evaluating high-risk features. A previous study from India reported only 9% (28/326) cases with scleral or extrascleral infiltration.[3] Further, there are very few studies addressing this issue, and hence, there is considerable confusion regarding optimal treatment.[2,4] A recent prospective study by the Children’s Oncology Group, evaluating outcomes of standard dose adjuvant chemotherapy regime with vincristine, etoposide, and carboplatin, shows significantly increased risk of recurrence in cases of PLONI with MCH in the peri-papillary area.[4] However, no comment was made for cases with scleral invasion. Scleral invasion may involve varying width of sclera. The AJCC 8th edition classification grades scleral invasion as pT3c for scleral involvement limited to inner 2/3rd, and pT3d for tumors invading full-thickness sclera and/or invasion of emissary channels. Studies evaluating outcomes based on AJCC criteria have shown worst survival outcomes for pT3c and pT3d compared with pT2 and pT3a with six cycles of chemotherapy.[5,6] There is possible risk of missing extrascleral extension in cases with outer scleral involvement. Should these be given radiotherapy? This question remains unanswered as of now. We retrospectively reviewed the cases with scleral invasion at our center in the last 10 years (2016–2025) and found eight cases. Review of pathology slides confirmed scleral invasion in all cases. Three cases however also had extrascleral and/or cut end involvement and hence were excluded. At our center, currently, scleral involvement is treated with six cycles of adjuvant standard dose VEC chemotherapy. The patient characteristics, histopathological features, and outcomes for five patients with scleral invasion are provided in Table 1.Table 1: Clinical, histopathological features, and outcomes of retinoblastoma cases with scleral invasionAll five patients (2F, 3M; mean age: 2.94 years, median age: 3 years) had intraocular retinoblastoma. One of them had bilateral involvement, while the others were unilateral. All of them underwent upfront enucleation. (Note: Patients of bilateral RB underwent enucleation in the eye with Group E Retinoblastoma). Histopathological examination revealed poorly differentiated RB in all five cases. Sclera was involved to varying degrees in all the patients. All five had tumor-free optic nerve cut ends. Three patients had PLONI. All five patients were advised adjuvant chemotherapy of six cycles. All except one completed the six cycles; one patient expired after the first cycle. It is notable that 2/3 (67%) cases of scleral invasion that were associated with PLONI died of disease, one of orbital recurrence with CNS metastasis and the other of systemic metastasis at mean follow-up of 8 months. The third case has a follow-up of only 6 months at this time and is being kept on close follow-up. The two cases with scleral invasion alone are alive at the last follow-up of 3 and 8 years, respectively. One of them had a full thickness scleral invasion, while the other had focal scleral invasion. It appears that isolated scleral involvement without PLONI may be observed with standard adjuvant chemotherapy, but scleral involvement along with PLONI could be a cause of alarm. Providing more intensive chemotherapy or EBRT in addition to the standard chemotherapy in this subset may perhaps help salvaging life. This needs to be investigated further. Authors’ contributions Rachna Meel: Concepts, Design, Definition of intellectual content, Literature search, Clinical studies, Data acquisition, Data analysis, Manuscript preparation, Manuscript editing, Manuscript review, Guarantor; Keerthana Kasi: Concepts, Design, Definition of intellectual content, Literature search, Clinical studies, Data acquisition, Data analysis, Manuscript preparation, Manuscript editing, Manuscript review, Guarantor; Seema Kashyap: Concepts, Design, Definition of intellectual content, Literature search, Clinical studies, Data acquisition, Data analysis, Manuscript preparation, Manuscript editing, Manuscript review, Guarantor; Sameer Bakhshi: Concepts, Design, Definition of intellectual content, Literature search, Clinical studies, Data acquisition, Data analysis, Manuscript preparation, Manuscript editing, Manuscript review, Guarantor. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.