The management of retinoblastoma is complex. With increasing treatment modalities and increasing experience with each treatment modality, the globe salvage rates have drastically improved with time. Aqueous seeding in an eye with retinoblastoma is classified as group E based on International Classification of Intraocular Retinoblastoma, and most group E eyes were enucleated a decade earlier. Newer modalities of treatment have improved the globe salvage rates in group E eyes including those with aqueous seeding. Various globe salvage treatment modalities attempted for the management of aqueous seeds include external beam radiotherapy, plaque radiotherapy, intra-arterial chemotherapy, periocular chemotherapy, intravitreal chemotherapy and intracameral chemotherapy. Of all treatment modalities, intracameral chemotherapy holds promise for the management of aqueous seeds in selected patients, but it should be done with the utmost care by a trained ocular oncologist. Enucleation is still the preferred modality of treatment for eyes with advanced retinoblastoma and anterior segment invasion. This review focuses on the current evidence on aqueous seeding, highlighting the pathogenesis, classification, clinical presentation, treatment and outcomes.
To discuss the clinical presentation, management, and outcome of delayed metastasis in retinoblastoma (RB).
Retrospective case series of three patients.
Mean age at diagnosis of RB was 29 months (median, 28 months; range, 11–48 months). All were males with non-familial bilateral intraocular RB. Primary treatment for RB included intravenous chemotherapy in all three cases. Secondary treatment included transpupillary thermotherapy/cryotherapy (n = 6 eyes), periocular chemotherapy (n = 2 eyes), intravitreal chemotherapy (n = 1 eye), intra-arterial chemotherapy (n = 1 eye), external beam radiotherapy (EBRT; n = 2 eyes), and enucleation (n = 2 eyes). Primary tumor regression was achieved in all cases and remained status quo at the time of diagnosis of distant metastasis. Two patients developed bone metastasis (ulna; tibia) and one developed soft tissue metastasis (temporal fossa) over a mean follow-up period of 6 years (median, 7 years; range, 5–8 years) from diagnosis of RB. Mean age of detection of metastatic disease was 8 years (median, 8 years; range, 7–9 years). All the lesions were solitary and the diagnosis of metastatic retinoblastoma was confirmed by tissue biopsy. Metastatic disease was treated with surgical excision (n = 1), chemotherapy (n = 2), and EBRT (n = 2). All patients are alive, with two patients free of disease over a mean follow-up period of 23 months (median, 23 months; range, 12–33 months); and 1 in remission 7 months after completion of EBRT.
Long-term follow-up of RB cases is mandatory. In spite of intraocular tumor regression, metastasis can still occur many years after treatment of RB.
The purpose of this study was to screen target miRNA related to RB and explore the expression levels of target miRNA in RB and its potential value of diagnosis.
The Affymetrix GeneChip miRNA 4.0 Array was used to screen the differential miRNAs in the plasma of 5 RB patients before and after intravenous chemotherapy, and the most significant down-regulated miRNA was selected for target miRNA. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) is used to verify the expression levels of plasma target miRNA in 30 RB patients. Then, qRT-PCR was performed to further verify the expression of target miRNA in plasma of RB patients and RB tumor tissues. Finally, receiver-operating-characteristic (ROC) curve and the area under the ROC curve (AUC) were used to evaluate the diagnostic power of plasma target miRNA.
The miRNA Array obtain 8 core miRNAs, 1 up-regulated and 7 down-regulated, of which miR-6089 was the most significantly down-regulated. Plasma miR-6089 levels were significantly up-regulated in RB patients. Besides, in RB tumor tissues, miR-6089 levels were also obviously up-regulated. After intravenous chemotherapy, the expression of plasma miR-6089 was significantly decreased. Furthermore, ROC curve analysis showed that miR-6089 in the plasma had a good sensitivity and specificity for distinguishing RB from the healthy control group.
MiR-6089 may be considered as a novel potential diagnostic biomarker for RB.
To analyze the risk factors and estimate the risk period for tumor recurrence in intraocular retinoblastoma (RB).
Retrospective study of 60 RB patients.
The mean age at presentation with RB was 16 months (median 11 months; range 1–84 months). Tumor was unilateral in 13 (22%) and bilateral in 47 (78%) patients. Of 83 eyes with intraocular RB, group B (n = 27; 33%) tumors were more common based on International Classification of Intraocular Retinoblastoma. All cases received intravenous chemotherapy as a primary treatment. Over a mean follow-up period of 57 months (median 38 months; range 12–185 months) post-primary treatment, 44 (73%) patients developed tumor recurrence. The mean interval between the completion of primary treatment and first tumor recurrence was 5 months (median 3 months; range 1–24 months). The total duration of treatment for complete tumor control including treatment of tumor recurrences was 20 months (median 19 months; 2–58 months). By multivariate analysis, the factors predictive of tumor recurrence were multiple tumors (p = 0.008) and retinal detachment (p = 0.003) at presentation. Kaplan–Meier estimate of tumor recurrence at 6 months, 1 year, 3 years, and 5 years was 20%, 31%, 68%, and 73%, respectively. There was no tumor recurrence beyond 5 years since primary treatment.
Multiple tumors and retinal detachment at presentation are risk factors for tumor recurrence in RB. Close follow-up is mandatory for at least 5 years since the initiation of treatment for RB.
Dhingra, Himani; Arya, Deepanjali; Taluja, Ankit; Das, Sima; Mahajan, AmitaRead More
Retinoblastoma (RB) is the commonest intraocular tumor in children. Despite high cure rates, data on health-related quality of life (HRQoL) of RB survivors are limited. This study aimed to analyze parent’s perspective and self-report of HRQoL of RB survivors, using healthy siblings as controls. It also evaluated the impact of socio-economic status (SES), gender, disease laterality, treatment modality, duration since diagnosis, and visual outcomes, on HRQoL.
Ninety-two RB survivors were enrolled in this observational, cross-sectional questionnaire-based study conducted at a tertiary care center. QoL was analyzed in four dimensions: physical, emotional, social, and school, using both self-report (for children >6 years) and parent proxy report (for children 2–18 years) using Pediatric Quality of Life Inventory™ (PedsQL™) 4.0 Generic Core Scale. Seventy-seven healthy siblings served as controls.
The mean age of both cohorts was 5.7 years. Thirty-six (39%) patients had bilateral RB. Of the 92 survivors, 43 (47%) had undergone enucleation. The HRQoL of RB survivors was significantly lower compared to sibling controls (P < 0.01) in all four domains, the physical domain being most affected followed by social domain. Parents reported an inferior QoL than patient’s self-report. Vision <6/18 in the best eye and enucleation had a negative impact on HRQoL whilst gender, disease laterality, duration since diagnosis and SES had no impact.
QoL assessment is often neglected but an important aspect of survivorship. Results of our study will help in formulating awareness of the domains affected and allow timely advocacy of initiatives for addressing each issue individually. Remedial measures aimed at optimizing QoL should be incorporated as part of their rehabilitation.
Christina Stathopoulos, Alexandre Moulin, Francis L. MunierRead More
A 3-year-old boy with unilateral retinoblastoma Group D was seen after 3 cycles of systemic chemotherapy given elsewhere. Slit-lamp examination revealed anterior-chamber seeding (Fig A). Anterior-segment OCT distinguished tumor-free (Fig B) from invaded (Fig C) Schlemm’s canal (arrows), which was confirmed after enucleation on histopathology (Figs B’and C’). Adjuvant chemotherapy to prevent metastasis is planned. This ongoing case illustrates that OCT can accurately delineate retinoblastoma extent in the anterior segment in vivo (Magnified version of Fig A-C is available online at www.aaojournal.org).
Christina Stathopoulos, Bruno Bartolini, Guillaume Marie, Maja Beck-Popovic, Guillaume Saliou, Francis L. MunierRead More
To identify risk factors for acute choroidal ischemia (ACI) after intra-arterial chemotherapy (IAC) for retinoblastoma.
Retrospective cohort study.
Two hundred twenty patients (248 eyes) treated with IAC in Lausanne between November 2008 and September 2019 (665 procedures). All patients were evaluated on a monthly basis with fundus photography and fluorescein angiography before and after each IAC injection.
Acute choroidal ischemia, defined as any new choroidal ischemia clinically diagnosed within 35 days after an IAC injection, were noted. Eyes with choroidal complications diagnosed later than 35 days after the last IAC injection (n = 7) or those for which the status of the choroid was not assessable (n = 35) were excluded. Specific procedure parameters and treatment regimens were compared between the group of eyes with and without ACI.
Main Outcome Measures
Procedure-related risk factors for ACI after IAC injection and visual acuity assessment in the group of eyes with ACI.
Acute choroidal ischemia developed in 35 of 206 included eyes after a mean of 2 injections. No differences were found between the two study groups regarding age at first IAC injection, disease grouping at diagnosis, previously administered treatments, number of IAC injections, drug dose, mean injection time, injection method (pulsatile vs. continuous), or concomitant intravitreal melphalan use. Treatment regimen (melphalan vs. combined melphalan plus topotecan; P < 0.05), catheterization route (internal carotid artery vs. external carotid or posterior communicating artery; P < 0.001), and catheterization type (occlusive into the ophthalmic artery [OA] vs. nonocclusive; P < 0.001) were included in multivariate analysis, and occlusive catheterization was identified as an independent risk factor for ACI (P < 0.001). In the subgroup undergoing an occlusive procedure, placement of the catheter tip into the OA distal third versus medial and proximal thirds (P = 0.04) and a mean catheter diameter-to-OA lumen ratio of 0.6 or more (P < 0.001) were correlated significantly with ACI. Complete vision loss was noted in 27% of the eyes with ACI that were old enough for visual assessment (n = 9/33), whereas 33% maintained a useful vision ranging between 0.1 and 0.8 (n = 11/33).
Catheterization of the OA should be attempted from an ostial position or an external carotid approach to minimize the risk of potentially vision-threatening choroidal complications.
Ankit Singh Tomar, Paul T. Finger…….. American Joint Committee on Cancer Ophthalmic Oncology Task ForceRead More
To compare metastasis-related mortality, local treatment failure, and globe salvage after retinoblastoma in countries with different national income levels.
International, multicenter, registry-based retrospective case series.
Two thousand one hundred ninety patients, 18 ophthalmic oncology centers, and 13 countries on 6 continents.
Multicenter registry-based data were pooled from retinoblastoma patients enrolled between January 2001 and December 2013. Adequate data to allow American Joint Committee on Cancer staging, eighth edition, and analysis for the main outcome measures were available for 2085 patients. Each country was classified by national income level, as defined by the 2017 United Nations World Population Prospects, and included high-income countries (HICs), upper middle-income countries (UMICs), and lower middle-income countries (LMICs). Patient survival was estimated with the Kaplan-Meier method. Logistic and Cox proportional hazards regression models were used to determine associations between national income and treatment outcomes.
Main Outcome Measures
Metastasis-related mortality and local treatment failure (defined as use of secondary enucleation or external beam radiation therapy).
Most (60%) study patients resided in UMICs and LMICs. The global median age at diagnosis was 17.0 months and higher in UMICs (20.0 months) and LMICs (20.0 months) than HICs (14.0 months; P < 0.001). Patients in UMICs and LMICs reported higher rates of disease-specific metastasis-related mortality and local treatment failure. As compared with HICs, metastasis-related mortality was 10.3-fold higher for UMICs and 9.3-fold higher for LMICs, and the risk for local treatment failure was 2.2-fold and 1.6-fold higher, respectively (all P < 0.001).
This international, multicenter, registry-based analysis of retinoblastoma management revealed that lower national income levels were associated with significantly higher rates of metastasis-related mortality, local treatment failure, and lower globe salvage.
Primary orbital polymethylmethacrylate implant following primary enucleation for retinoblastoma: a study of 321 cases
Purpose: To evaluate the outcome of primary orbital polymethylmethacrylate (PMMA) implant following the primary enucleation for retinoblastoma.
Methods: Retrospective study of 321 retinoblastoma patients who underwent unilateral enucleation and PMMA implant for retinoblastoma by myoconjunctival technique. Outcome measures included implant centration and extrusion.
Results: The mean age at the time of enucleation of patients with retinoblastoma was 35 months (median, 30 months; range, <1 to 449 months). After primary enucleation, primary orbital PMMA implant was used in all cases. The mean diameter of implant was 18 mm (median, 18 mm; range, 12–20 mm) and the mean horizontal diameter of the socket conformer was 24 mm (median, 24 mm; range, 18 mm–26 mm). Post-enucleation and implant, seven (2%) patients underwent orbital external beam radiotherapy owing to microscopic extrascleral tumor extension or tumor infiltration of optic nerve transection. Over a mean follow-up period of 40 months (median, 34 months; range, 4–129 months), implant migration was noted in 28 (9%) patients, implant extrusion in 9 (3%), and implant exposure in 5 (2%), and contracted socket in 5 (2%) patients including grade 1 contraction in 3 (1%), grade 2 in 1 (<1%), and grade 4 in 1 (<1%) patient. Implant exchange for an improved prosthesis fit was performed in 4 (1%) cases. Stable customized ocular prosthesis was achieved in all but one patient.
Conclusion: Primary orbital PMMA implant following primary enucleation for retinoblastoma is associated with minimal complications and provides acceptable cosmetic outcomes.
Erica L. Friedman; Michael T. Froehler, MD, PhD; Anthony B. Daniels, MD, MScRead More
A 9-month-old girl presented to the emergency department with significant left periocular edema and erythema 3 days after receiving intra-arterial chemotherapy (IAC) with 0.4 mg/kg of melphalan, 50 mg of carboplatin, and 2 mg of topotecan (with routine intravenous dexamethasone therapy, 0.5 mg/kg) for treatment of unilateral International Classification of Retinoblastoma group C retinoblastoma in the left eye (Figure, A). At the time of IAC, she had an upper respiratory tract infection (coughing, congestion, rhinorrhea, fever [temperature of 38.9 °C]). On postoperative day 1, her temperature reached 39.4 °C, and she was diagnosed as having bilateral acute otitis media and discharged with amoxicillin therapy. On postoperative day 3, she returned to the emergency department with left eye swelling, continued fever, and poor oral intake. On physical examination, her temperature was 40.2 °C, and periorbital swelling and erythema were present without drainage. Dilated fundus examination at the bedside showed the known large retinoblastoma tumor. A large exudative retinal detachment was noted, which was not present prior to treatment. Blood bacterial culture testing showed no growth, respiratory viral testing revealed rhinovirus, and results of comprehensive metabolic testing were unremarkable. Complete blood cell count showed mild leukopenia (2700/μL [to convert to ×109 per liter, multiply by 0.001]) and anemia (hemoglobin, 9.2 g/dL [to convert to grams per liter, multiply by 10]) but were otherwise within reference ranges. Computed tomography scan of the orbits, recommended by the on-call general ophthalmologist, demonstrated preseptal and periorbital soft tissue swelling and edema with subtle retrobulbar stranding, without substantial proptosis, along with retinal detachment (Figure, B). She was admitted for intravenous fluids for her noted dehydration.