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Retinoblastoma is a rare tumour of the eye which develops in the cells of the retina, most patients are under 5 years old. Sometimes only one eye is affected (unilateral-retinoblastoma ), but in about two fifths of patients both eyes have the disease (bilateral-retinoblastoma ). Some cases are known to be hereditary.

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Park SJ, Woo SJ, Park KH
Incidence of retinoblastoma and survival rate of retinoblastoma patients in Korea using the Korean National Cancer Registry database (1993-2010).
Invest Ophthalmol Vis Sci. 2014; 55(5):2816-21 [PubMed] Related Publications
PURPOSE: We determined the incidence of retinoblastoma and the long-term survival rate of retinoblastoma patients in South Korea.
METHODS: We reviewed retrospectively data from the Korea Central Cancer Registry recorded between 1993 and 2010 to identify the incidence of retinoblastoma and the survival rate of retinoblastoma patients in Korea. The incidence of retinoblastoma was estimated by population-based analysis of children aged 0 to 4 years and children aged 0 to 9 years, population-based analysis per live birth, and birth cohort analysis. Survival was analyzed using the Korea Central Cancer Registry database, which was crosschecked with the national death registry.
RESULTS: The overall incidence was 11.2 for children aged 0 to 4 years and 5.3 for children aged 0 to 9 years per 1,000,000 person-years, 5.9 per 100,000 live births, and 5.3 per 100,000 live births. Birth cohort analysis showed less variable results in incidence rates over 4 calendar-periods compared to the population-based analyses. The all-cause mortality rate was 7.9% at 5 years and 8.4% at 10 years. The rate improved from 12.5% for patients diagnosed in 1993 to 2000 to 4.5% for those diagnosed in 2001 to 2010.
CONCLUSIONS: The incidence of retinoblastoma in Korea was found to be similar to that in the United States, Europe, and Asia. The survival rate of retinoblastoma patients in Korea was significantly better during 2001 to 2010 than during 1993 to 2000.

Brown L
Recognising retinoblastoma: what health visitors need to know.
Community Pract. 2014; 87(3):42-5 [PubMed] Related Publications
Retinoblastoma is very rare, with between 40 and 50 cases in the UK each year. However, delays in diagnosis and treatment can lead to loss of vision or even death, while with prompt treatment the outcome is much more positive. This article aims to provide community practitioners with the correct information about retinoblastoma, ensuring that babies and young children with retinoblastoma are identified at the first sign of the disease and are referred promptly. The article will examine the signs and symptoms of retinoblastoma, consider treatment options, present a case study and explore the role of the health visitor.

Wong JR, Tucker MA, Kleinerman RA, Devesa SS
Retinoblastoma incidence patterns in the US Surveillance, Epidemiology, and End Results program.
JAMA Ophthalmol. 2014; 132(4):478-83 [PubMed] Related Publications
IMPORTANCE Several studies have found no temporal or demographic differences in the incidence of retinoblastoma except for age at diagnosis, whereas other studies have reported variations in incidence by sex and race/ethnicity. OBJECTIVE To examine updated US retinoblastoma incidence patterns by sex, age at diagnosis, laterality, race/ethnicity, and year of diagnosis. DESIGN, SETTING, AND PARTICIPANTS The Surveillance, Epidemiology, and End Results (SEER) databases were examined for retinoblastoma incidence patterns by demographic and tumor characteristics. We studied 721 children in SEER 18 registries, 659 in SEER 13 registries, and 675 in SEER 9 registries. MAIN OUTCOMES AND MEASURES Incidence rates, incidence rate ratios (IRRs), and annual percent changes in rates. RESULTS During 2000-2009 in SEER 18, there was a significant excess of total retinoblastoma among boys compared with girls (IRR, 1.18; 95% CI, 1.02 to 1.36), in contrast to earlier reports of a female predominance. Bilateral retinoblastoma among white Hispanic boys was significantly elevated relative to white non-Hispanic boys (IRR, 1.81; 95% CI, 1.22 to 2.79) and white Hispanic girls (IRR, 1.75; 95% CI, 1.11 to 2.91) because of less rapid decreases in bilateral rates since the 1990s among white Hispanic boys than among the other groups. Retinoblastoma rates among white non-Hispanics decreased significantly since 1992 among those younger than 1 year and since 1998 among those with bilateral disease. CONCLUSIONS AND RELEVANCE Although changes in the availability of prenatal screening practices for retinoblastoma may have contributed to these incidence patterns, further research is necessary to determine their actual effect on the changing incidence of retinoblastoma in the US population. In addition, consistent with other cancers, an excess of retinoblastoma diagnosed in boys suggests a potential effect of sex on cancer origin.

Related: USA

Manjandavida FP, Honavar SG, Reddy VA, Khanna R
Management and outcome of retinoblastoma with vitreous seeds.
Ophthalmology. 2014; 121(2):517-24 [PubMed] Related Publications
PURPOSE: To report the treatment response of retinoblastoma with vitreous seeds to high-dose chemotherapy coupled with periocular carboplatin.
DESIGN: Retrospective, interventional case series.
PARTICIPANTS: Consecutive patients with retinoblastoma with vitreous seeds managed over 10 years at a comprehensive ocular oncology center and followed up for at least 12 months after the completion of treatment were included in this study. Institutional review board approval was obtained.
INTERVENTION: High-dose chemotherapy with a combination of vincristine, etoposide, and carboplatin in patients with focal vitreous seeds and additional concurrent periocular carboplatin in patients with diffuse vitreous seeds.
MAIN OUTCOME MEASURES: Tumor regression, vitreous seed regression, and eye salvage.
RESULTS: After excluding the better eye of bilateral cases, 101 eyes of 101 patients were part of the final analysis. All the patients belonged to Reese-Ellsworth group VB, but on the International Classification of Retinoblastoma (ICRB), 21 were group C, 40 were group D, and 40 were group E. The mean basal diameter of the largest tumor was 11.8 ± 4.7 mm. Mean tumor thickness was 7.5 ± 4.0 mm. Vitreous seeds were focal in 21 eyes and diffuse in 80 eyes. Chemotherapy cycles ranged from 6 to 12 (median, 6). Seventy-three eyes with diffuse vitreous seeds received a 15-mg posterior sub-Tenon carboplatin injection (range, 1-13 mg; median, 6 mg). Follow-up duration ranged from 13.4 to 129.2 months (median, 48 months). External beam radiotherapy (EBRT) was necessary in 33 eyes with residual tumor, vitreous seeds, or both. In all, 20 eyes (95%) with ICRB group C retinoblastoma, 34 eyes (85%) with group D retinoblastoma, and 23 eyes (57.5%) with group E retinoblastoma were salvaged. Of 77 eyes that were salvaged, 74 (96%) had visual acuity of 20/200 or better. Twenty-four of 33 chemotherapy failures (73%) regressed with EBRT. None of the patients demonstrated second malignant neoplasm or systemic metastasis. Factors predicting tumor regression and eye salvage were bilateral retinoblastoma and absence of subretinal fluid. Factors predicting vitreous seed regression were absence of subretinal fluid and subretinal seeds.
CONCLUSIONS: Intensive management with primary high-dose chemotherapy and concurrent periocular carboplatin, and EBRT selectively in chemotherapy failures, provides gratifying outcome in retinoblastoma with vitreous seeds.

Related: Carboplatin Etoposide Vincristine

Kalita D, Shome D, Jain VG, et al.
In vivo intraocular distribution and safety of periocular nanoparticle carboplatin for treatment of advanced retinoblastoma in humans.
Am J Ophthalmol. 2014; 157(5):1109-15 [PubMed] Related Publications
PURPOSE: To study the intraocular distribution and safety of polymethylmethacrylate nanoparticles loaded with carboplatin after posterior subtenon injection in humans.
DESIGN: Prospective, interventional, comparative case series.
METHODS: Six patients (mean age: 26.83 ± 7.5 years), scheduled to undergo planned uniocular enucleation in an institutional setting, were randomly divided into 3 groups. Each group received a 10 mg/mL posterior subtenon injection of nanoparticle carboplatin in the eye to be enucleated. Two eyes were enucleated 6, 24 and 72 hours post injection. Intravenous blood was collected during enucleation. The concentration of carboplatin reaching various intraocular tissues was determined by inductively coupled plasma atomic emission spectroscopy. The drug toxicity in the ocular tissues was assessed by histopathology and high-resolution transmission electron microscopy.
RESULTS: The highest level of carboplatin was detected in retinas (8.33 ± 1.69 mg/g), up to 24 hours post treatment. The intravitreal concentration continued to increase gradually until 72 hours (3.46 ± 0.26 mg/g). The choroids and lenses showed very low levels of carboplatin after 6 hours, with negligible amounts at 72 hours. No signs of tissue damage were observed on histopathology or electron microscopy. Intravenous concentration of carboplatin was undetectable in all patients.
CONCLUSION: Results may indicate an increased facilitated trans-scleral transport of nanoparticle carboplatin, with a sustained-release behavior but without any associated short-term ocular or systemic side effects in humans. The very high concentrations achieved in vitreous and retina after a single posterior subtenon injection may be clinically useful for adjunctive treatment of advanced intraocular retinoblastoma with vitreous seeds. However, further studies are needed to assess long-term toxicity and clinical efficacy.

Related: Carboplatin

Chawla B, Khurana S, Sen S, Sharma S
Clinical misdiagnosis of retinoblastoma in Indian children.
Br J Ophthalmol. 2014; 98(4):488-93 [PubMed] Related Publications
AIM: To determine the rate of clinical misdiagnosis in paediatric patients who were enucleated for retinoblastoma and report the clinicopathological features of cases that were misdiagnosed.
METHODS: Retrospective review of medical records of children who underwent a primary enucleation for advanced retinoblastoma was done. In all cases, the diagnosis of retinoblastoma was made on the basis of clinical presentation and imaging modalities. Clinicopathological features of eyes with discordant clinical and histopathological diagnosis were studied in detail.
RESULTS: Of 280 eyes (280 patients) that were enucleated over a 4-year period, histopathological diagnosis was consistent with retinoblastoma in 276 (98.6%) eyes. In 4 (1.4%) eyes, clinical and histopathological diagnoses were discordant. Histopathological features in misdiagnosed cases included one case each of granulomatous endophthalmitis, retinal astrocytoma, Coats' disease and persistent hyperplastic primary vitreous.
CONCLUSIONS: To the best of our knowledge, this is the first study to examine the rate of clinical misdiagnosis of retinoblastoma from South Asia. Despite the use of modern preoperative imaging modalities including MRI scans, benign lesions in end-stage conditions simulated retinoblastoma, resulting in potentially avoidable enucleation.

D'Elia G, Grotta S, Del Bufalo F, et al.
Two novel cases of trilateral retinoblastoma: genetics and review of the literature.
Cancer Genet. 2013; 206(11):398-401 [PubMed] Related Publications
Retinoblastoma (RB) is the most common eye tumor in children; it originates from germline and/or somatic mutations that inactivate both alleles of the RB1 gene located on chromosome 13q14. Patients with unilateral or bilateral RB infrequently may develop an additional intracranial neuroblastic tumor, usually in the pineal gland, which characterizes the trilateral retinoblastoma (TRB) syndrome. The most common chromosomal abnormalities detected in TRB are deletions at 13q14, even if some rare cases of RB1 point mutations were described. In our report, we investigated two patients with TRB who showed a germline RB1 point mutation that has never been found to date and a large deletion involving RB1, respectively. Genetic data were compared to our in-house series and to current literature; these data suggested a role for other candidate regions in the pathogenesis of TRB. Moreover, our study highlights the need for new approaches allowing a multigenic analysis to clarify the genotype-phenotype correlation in TRB.

Related: Cancer Cytogenetics

Shields CL, Manjandavida FP, Arepalli S, et al.
Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results.
JAMA Ophthalmol. 2014; 132(3):319-25 [PubMed] Related Publications
IMPORTANCE: Recurrent or persistent vitreous seeds following treatment of retinoblastoma poses difficult management and often leads to enucleation.
OBJECTIVE: To describe the technique and evaluate the efficacy and complications of intravitreal melphalan for vitreous seeding from retinoblastoma.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective noncomparative analysis was conducted at a tertiary referral center. The study included 11 consecutive eyes of 11 patients with viable persistent or recurrent vitreous seeds following treatment of retinoblastoma.
INTERVENTIONS: All eyes received intravitreal melphalan injection (20-30 µg) by transconjunctival pars plana route with concomitant triple-freeze cryotherapy at the injection site during needle withdrawal for prevention of extraocular seeding. Each patient was offered planned 6 monthly cycles.
MAIN OUTCOMES AND MEASURES: Vitreous seed control and complications of therapy.
RESULTS: The mean patient age at vitreous injection was 37 months (median, 27 months; range, 16-82 months). Viable vitreous seeds involved 2 (n = 1), 3 (n = 4), or 4 (n = 6) quadrants. The solid intraretinal retinoblastoma and subretinal seeds showed regression in all eyes following intravenous chemotherapy (n = 6) or intra-arterial chemotherapy (n = 5). There were a total of 55 injections, with a mean number per patient of 5 (median, 6; range, 2-6). Fewer than 6 injections (n = 5) were delivered owing to complete vitreous seed control and parental desire to avoid more injections. By a mean of 9 months' follow-up (median, 9 months; range, 6-16 months), therapeutic success with complete vitreous seed regression was achieved in all 11 cases (100%). Globe salvage was attained in all cases (100%). Further vitreous seed development did not occur in any case. Complications included focal retinal pigment epithelial mottling near the site of chemotherapy injection (2 eyes) and nonaxial posterior lens opacity (2 eyes). There was no case of extraocular tumor extension, hypotony, or phthisis bulbi.
CONCLUSIONS AND RELEVANCE: These preliminary short-term results suggest that intravitreal melphalan injection for persistent or recurrent vitreous retinoblastoma seeding can provide tumor control with minimal toxicity and complications.

Related: Melphalan

Sudhakar J, Khetan V, Madhusudan S, Krishnakumar S
Dysregulation of human apurinic/apyrimidinic endonuclease 1 (APE1) expression in advanced retinoblastoma.
Br J Ophthalmol. 2014; 98(3):402-7 [PubMed] Related Publications
BACKGROUND: Retinoblastoma (RB) is a childhood eye tumour. Dysregulation of DNA repair may not only influence pathogenesis but could also adversely impact on response to cytotoxic chemotherapy frequently used in RB therapy. We studied the expression of human apurinic/apyrimidinic endonuclease (APE1), a key multifunctional protein involved in DNA base excision repair in RB.
METHODS: Expression of APE1 was evaluated by immunohistochemistry in a series of 55 RBs and in retina. In tumours, APE1 expression was analysed in cytoplasm and nucleus independently and correlated with histopathological features, including invasion, differentiation and International Intraocular Retinoblastoma Classification groups. Relative APE1 mRNA and protein expressions were evaluated by real-time PCR and western blot. The expression of APE1 in tumour groups was compared with retinal tissue.
RESULTS: APE1 cytoplasmic expression was observed in 98% and nuclear positivity was observed in 83% of tumours analysed. Tumour cells invading the optic nerve showed predominant cytoplasmic immunoreactivity. An inverse correlation between cytoplasmic and nuclear positivity was observed. Real-time PCR revealed an increase in APE1 transcripts compared with retina. Western blot revealed a decreased protein concentration compared with retinal tissue.
CONCLUSIONS: This is the first study of APE1 expression in RB. Our observation suggests that subcellular localisation of APE1 is altered in RB. APE1 could be a potential drug target in RB.

Yunoki T, Tabuchi Y, Hayashi A, Kondo T
Inhibition of polo-like kinase 1 promotes hyperthermia sensitivity via inactivation of heat shock transcription factor 1 in human retinoblastoma cells.
Invest Ophthalmol Vis Sci. 2013; 54(13):8353-63 [PubMed] Related Publications
PURPOSE: Hyperthermia (HT) has been recognized as an effective focal treatment in retinoblastoma. However, one of the problems with HT therapy is that cells acquire acquisition. The purpose of this study was to evaluate whether the inhibition of polo-like kinase 1 (PLK1) would promote HT sensitivity in human retinoblastoma cells.
METHODS: We examined the effects of PLK1 knockdown by small interfering RNA (siRNA) or by the inhibition of PLK1 activity with PLK1 inhibitor (BI-2536) on the sensitivity to HT (44°C, 1 hour) in human retinoblastoma Y79 and WERI-Rb-1 cells by evaluating apoptosis and cell proliferation using flow cytometry, Western blotting, real-time quantitative polymerase chain reaction, and WST-8 assay. Furthermore, we investigated the effects of activating heat shock transcription factor 1 (HSF1) through a combination of PLK1 knockdown and HT using Western blotting and immunocytochemistry.
RESULTS: The combination of PLK1 inhibition and HT enhanced sensitivity to HT synergistically. Furthermore, PLK1 knockdown inhibited HT-induced phosphorylation of HSF1, the nuclear translocation of HSF1 from the cytoplasm, and nuclear granule formation of HSF1. Heat shock transcription factor 1, inactivated by the silencing of PLK1, reduced the expression of heat shock proteins (HSPs), such as HSP70 and HSP40, as well as the expression of Bcl-2-associated athanogene 3 (BAG3).
CONCLUSIONS: Polo-like kinase 1 inhibition may attenuate the thermoresistance of HT through the inactivation of HSF1 concomitant with reductions in HSPs and BAG3. The combination of PLK1 inhibition and HT may become an option for HT therapy in patients with retinoblastoma.

Related: Apoptosis

Taich P, Ceciliano A, Buitrago E, et al.
Clinical pharmacokinetics of intra-arterial melphalan and topotecan combination in patients with retinoblastoma.
Ophthalmology. 2014; 121(4):889-97 [PubMed] Related Publications
PURPOSE: To assess the antitumor activity, toxicity, and plasma pharmacokinetics of the combination of melphalan and topotecan for superselective ophthalmic artery infusion (SSOAI) treatment of children with retinoblastoma.
DESIGN: Single-center, prospective, clinical pharmacokinetic study.
PARTICIPANTS: Twenty-six patients (27 eyes) with intraocular retinoblastoma.
METHODS: Patients with an indication for SSOAI received melphalan (3-6 mg) and topotecan (0.5-1 mg; doses calculated by age and weight). Plasma samples were obtained for pharmacokinetic studies, and a population approach via nonlinear mixed effects modeling was used. Safety and efficacy were assessed and compared with historical cohorts of patients treated with melphalan single-agent SSOAI.
MAIN OUTCOME MEASURES: Melphalan and topotecan pharmacokinetic parameters and efficacy and safety parameters.
RESULTS: Twenty-seven eyes from 26 consecutive patients received 66 cycles of SSOAI melphalan and topotecan in combination. All 5 eyes treated as primary therapy responded to the combination chemotherapy and were preserved. Sixteen of the 22 eyes with relapsed or resistant tumors responded, but 3 of them ultimately underwent enucleation at a median of 8 months (range, 7.9-9.1 months). The incidence of grade III and IV neutropenia was 10.6% and 1.5%, respectively, which was comparable with historical controls of single-agent SSOAI melphalan. No episode of fever neutropenia was observed, and no patient required transfusion of blood products. The large variability in melphalan pharmacokinetics was explained by body weight (P <0.05). Concomitant topotecan administration did not influence melphalan pharmacokinetic parameters. There was no effect of the sequence of melphalan and topotecan administration in plasma pharmacokinetics.
CONCLUSIONS: A regimen combining melphalan and topotecan for SSOAI treatment of retinoblastoma is active and well tolerated. This combination chemotherapy previously showed synergistic pharmacologic activity, and we herein provide evidence of not increasing the hematologic toxicity compared with single-agent melphalan.

Related: Melphalan Topotecan

Yousef YA, Halliday W, Chan HS, et al.
No ocular motility complications after subtenon topotecan with fibrin sealant for retinoblastoma.
Can J Ophthalmol. 2013; 48(6):524-8 [PubMed] Related Publications
OBJECTIVE: To report our long-term experience with the local toxicity profile and ocular motility changes after treatment of intraocular retinoblastoma with subtenon topotecan chemotherapy.
DESIGN: Cross-sectional study.
PARTICIPANTS: Ten eyes in 8 patients with retinoblastoma treated with subtenon topotecan.
METHODS: We assessed potential complications in ocular motility in eyes with retinoblastoma treated with subtenon topotecan using forced duction testing under general anaesthesia. Eyes subsequently enucleated because of treatment failure were examined histologically.
RESULTS: Ten eyes in 8 patients with retinoblastoma treated with 1 to 4 injections of subtenon topotecan were examined repeatedly, with a mean follow-up period of 37 months. Ocular motility remained normal in all eyes by forced duction, with no observed persistent conjunctival congestion, abnormal ocular motility, or enophthalmos in retained eyes 3 years after last injection. Histopathologic examination of the 2 enucleated eyes did not reveal signs of orbital tissue necrosis or fibrosis.
CONCLUSIONS: Unlike subtenon carboplatin, subtenon topotecan therapy is not associated with long-term toxicity affecting ocular muscles or orbital soft tissue. No effect on ocular motility was observed.

Related: Topotecan

Wang J, Wang X, Li Z, et al.
MicroRNA-183 suppresses retinoblastoma cell growth, invasion and migration by targeting LRP6.
FEBS J. 2014; 281(5):1355-65 [PubMed] Related Publications
Our study demonstrates the downregulation of microRNA-183 (miR-183) in retinoblastoma (RB) tissues and RB cell lines compared with normal retinal tissues. The ectopic expression of miR-183 in the RB cell lines Y79, SO-RB50 and WERI-RB1 suppresses cell viability, migration and invasion. Furthermore, the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) was identified as a new target of miR-183, and restoration of the expression of LRP6 rescues the effects induced by miR-183 in RB cells. These results indicate that miR-183 targets and downregulates LRP6 in the growth, migration and invasion of RB cells.

Related: Apoptosis

Mol BM, Massink MP, van der Hout AH, et al.
High resolution SNP array profiling identifies variability in retinoblastoma genome stability.
Genes Chromosomes Cancer. 2014; 53(1):1-14 [PubMed] Related Publications
Both hereditary and nonhereditary retinoblastoma (Rb) are commonly initiated by loss of both copies of the retinoblastoma tumor suppressor gene (RB1), while additional genomic changes are required for tumor initiation and progression. Our aim was to determine whether there is genomic heterogeneity between different clinical Rb subtypes. Therefore, 21 Rb tumors from 11 hereditary patients and 10 nonhereditary Rb patients were analyzed using high-resolution single nucleotide polymorphism (SNP) arrays and gene losses and gains were validated with Multiplex Ligation-dependent Probe Amplification. In these tumors only a few focal aberrations were detected. The most frequent was a focal gain on chromosome 2p24.3, the minimal region of gain encompassing the oncogene MYCN. The genes BAZ1A, OTX2, FUT8, and AKT1 were detected in four focal regions on chromosome 14 in one nonhereditary Rb. There was a large difference in number of copy number aberrations between tumors. A subset of nonhereditary Rbs turned out to be the most genomic unstable, while especially very young patients with hereditary Rb display stable genomes. Established Rb copy number aberrations, including gain of chromosome arm 1q and loss of chromosome arm 16q, turned out to be preferentially associated with the nonhereditary Rbs with later age of diagnosis. In contrast, copy number neutral loss of heterozygosity was detected mainly on chromosome 13, where RB1 resides, irrespective of hereditary status or age. Focal amplifications and deletions and copy number neutral loss of heterozygosity besides chromosome 13 appear to be rare events in retinoblastoma.

Related: Chromosome 13 Chromosome 14

Chantada GL, Fandiño AC, Schvartzman E, et al.
Impact of chemoreduction for conservative therapy for retinoblastoma in Argentina.
Pediatr Blood Cancer. 2014; 61(5):821-6 [PubMed] Related Publications
BACKGROUND: Few studies were reported from developing countries regarding patient outcome and ocular survival in children with bilateral retinoblastoma treated with chemoreduction compared to external beam radiotherapy (EBRT).
PROCEDURE: We undertook a retrospective study of three treatment eras: (1) (1988-1995) n = 68 when EBRT was used as primary conservative therapy; (2) (1995-2003) n = 46 when carboplatin-based systemic chemoreduction was introduced and (3) (2003-2009) (n = 83) when additional periocular chemotherapy was added for advanced tumors and pre-enucleation chemotherapy was given for those with massive buphthalmia.
RESULTS: The probability of 5-year disease-free survival was 0.94 (95% confidence interval [CI] 0.91-0.98%) without significant differences among the three eras. Chemoreduction reduced the use of EBRT from 84.6% to 68.7% in eras 1 and 3, respectively (P = 0.008), which was more evident in cases with less advanced disease. Chemoreduction also significantly improved the 5-year probability of preservation of eyes with advanced disease from 0.13 (95% CI 0.04-0.27) during era 1 to 0.49 (95% CI 0.34-0.62) in era 3 (P < 0.0001). Chemoreduction was not associated with changes in the probability of extraocular relapse, which was reduced after the introduction of pre-enucleation chemotherapy. Second malignancies occurred in nine cases, acute myeloid leukemia being the most fatal one. Trilateral retinoblastoma occurred in three cases and all of them had been exposed to chemotherapy.
CONCLUSIONS: Chemoreduction reduced the need for EBRT in eyes with less advanced disease and improved the preservation of eyes with advanced disease while its effects on secondary malignancies or trilateral disease remain unclear.

Related: Brachytherapy Carboplatin Vincristine

Liu CY, Jonna G, Francis JH, et al.
Non-selectivity of ERG reductions in eyes treated for retinoblastoma.
Doc Ophthalmol. 2014; 128(1):13-23 [PubMed] Related Publications
PURPOSE: We have monitored retinal function in patients treated for retinoblastoma (primarily, but not exclusively by intra-arterial chemotherapy infusion) by electroretinography (ERG) recordings for the past 7 years. We here present data from 599 ERG studies of 108 patients, in which a complete ERG protocol including both photopic and scotopic recordings was performed, in justification of our frequent practice of reporting primarily 30-Hz photopic flicker amplitude data.
METHODS: Patients referred for treatment of retinoblastoma underwent ERG recordings during examination under anesthesia whenever possible: at baseline and following most treatment sessions. Correlations were calculated for the complete datasets between the four primary amplitude response parameters: photopic single flash b-wave, photopic 30-Hz flicker peak-to-trough, scotopic rod-isolating b-wave, and scotopic maximal flash b-wave.
RESULTS: Using our adaptation of the International Society for Clinical Electrophysiology of Vision-recommended standard ERG protocol, ERG responses of eyes of patients with untreated retinoblastoma or following traditional or intra-arterial treatment for retinoblastoma show very high correlations between 30-Hz flicker amplitude responses and three other standard photopic and scotopic ERG response amplitudes. Reductions in ERG amplitudes seen in these eyes following treatment show no significant difference between retinal dysfunction estimated using rod- or cone-dominated responses.
CONCLUSION: These observations support the use of photopic response amplitudes (especially in response to 30-Hz flicker) as the primary ERG outcome measure in studies of treated and untreated eyes with retinoblastoma when more complete ERG protocols may be impractical.

Related: Carboplatin Etoposide Vincristine

Smith SJ, Smith BD, Mohney BG
Ocular side effects following intravitreal injection therapy for retinoblastoma: a systematic review.
Br J Ophthalmol. 2014; 98(3):292-7 [PubMed] Related Publications
PURPOSE: To describe the ocular side effects in patients receiving intravitreal injection therapy (IViT) for retinoblastoma.
METHODS: PubMed (1946-present), Scopus (all years), Science Citation Index (1900-present) and Conference Proceedings Citation Index-Science (1990-present) electronic databases were searched to identify all published reports of therapeutic intravitreal injections for retinoblastoma in humans.
RESULTS: Ten studies with original IViT ocular side effect data were included in this systematic review. In these combined reports, a total of 1287 intravitreal injections were given to 306 eyes of 295 patients, with a mean follow-up of 74.1 months. Two hundred sixty-one (88.5%) patients received comparatively standard melphalan IViT doses (8-30 mcg). Ocular side effects occurred in 38 patients (17 significant, 21 minor). The proportion of patients experiencing potentially significant ocular side effects following standard melphalan IViT regimens was 0.031 (8/261; 95% CI 0.013 to 0.06). The side effects of these eight included iris atrophy in three, two each with chorioretinal atrophy and vitreous haemorrhage and one with retinal detachment. Of the other nine patients with significant complications, five experienced sight-threatening complications following dramatic dose escalations (four with melphalan, one with thiotepa), three experienced complications that are commonly associated with concurrent therapies given to these patients and one had a retinal detachment. Of the 61 patients receiving IViT via safety-enhancing injection techniques, all six significant side effects were either attributed to the therapeutic dose or confounded by concurrent treatments.
CONCLUSIONS: Significant ocular complications following IViT for retinoblastoma are uncommon, and this risk may be reduced further by the use of careful injection technique and standard dosing regimens. Care must be taken in the dosing of intravitreal treatments to avoid potentially irreversible vision loss.

Related: Melphalan

Barot M, Gokulgandhi MR, Pal D, Mitra AK
In vitro moxifloxacin drug interaction with chemotherapeutics: implications for retinoblastoma management.
Exp Eye Res. 2014; 118:61-71 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Retinoblastoma (RB) is a common malignant intraocular tumor primarily affecting children. Multidrug resistance (MDR) proteins (P-gp and MRPs) mediated chemoresistance have been considered as a major cause of treatment failure in treatment of RB. Ocular cells have shown good tolerability against moxifloxacin (MFX). Hence, the aim of present study was to investigate the effect of moxifloxacin on the functionality of MDR proteins. Furthermore, we have also examined an interaction of MFX with anticancer agents (Topotecan, etoposide and vinblastine) for RB treatment. For interaction of MFX with efflux transporter, model cell lines transfected with the efflux transporters (MDCK-MDR1 and MDCK-MRP2) were used to perform uptake and bi-directional transport experiments. Modulation of anticancer induced cell cytotoxicity, pro-inflammatory cytokines (IL-6 and IL-8) release and caspase-3 enzyme activity in presence of MFX was also evaluated. Result indicates that MFX is a substrate of both MDR1 and MRP2 efflux transporters. Furthermore elevation of anticancer uptake and bi-directional transport, reduction in IC50 cytotoxic value and modulation of antiproliferative and cytokines release in presence of MFX by anticancer agents was observed. Our results demonstrate that MFX may not only modulate the permeability of anticancer agents at efflux sites but it may also potentiate antiproliferative activity of anticancer agents in retinoblastoma cells. This study may be further extended to explore in vivo outcome of this finding.

Sethi RV, Shih HA, Yeap BY, et al.
Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy.
Cancer. 2014; 120(1):126-33 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
BACKGROUND: The leading cause of death among patients with hereditary retinoblastoma is second malignancy. Despite its high rate of efficacy, radiotherapy (RT) is often avoided due to fear of inducing a secondary tumor. Proton RT allows for significant sparing of nontarget tissue. The current study compared the risk of second malignancy in patients with retinoblastoma who were treated with photon and proton RT.
METHODS: A retrospective review was performed of patients with retinoblastoma who were treated with proton RT at the Massachusetts General Hospital or photon RT at Boston Children's Hospital between 1986 and 2011.
RESULTS: A total of 86 patients were identified, 55 of whom received proton RT and 31 of whom received photon RT. Patients were followed for a median of 6.9 years (range, 1.0 years-24.4 years) in the proton cohort and 13.1 years (range, 1.4 years-23.9 years) in the photon cohort. The 10-year cumulative incidence of RT-induced or in-field second malignancies was significantly different between radiation modalities (proton vs photon: 0% vs 14%; P = .015). The 10-year cumulative incidence of all second malignancies was also different, although with borderline significance (5% vs 14%; P = .120).
CONCLUSIONS: Retinoblastoma is highly responsive to radiation. The central objection to the use of RT, the risk of second malignancy, is based on studies of patients treated with antiquated, relatively nonconformal techniques. The current study is, to the authors' knowledge, the first to present a series of patients treated with the most conformal of the currently available external-beam RT modalities. Although longer follow-up is necessary, the preliminary data from the current study suggest that proton RT significantly lowers the risk of RT-induced malignancy.

Martin A, Jones A, Bryar PJ, et al.
MicroRNAs-449a and -449b exhibit tumor suppressive effects in retinoblastoma.
Biochem Biophys Res Commun. 2013; 440(4):599-603 [PubMed] Related Publications
Retinoblastoma is the most common pediatric cancer of the eye. Currently, the chemotherapeutic treatments for retinoblastoma are broad-based drugs such as vincristine, carboplatin, or etoposide. However, therapies targeted directly to aberrant signaling pathways may provide more effective therapy for this disease. The purpose of our study is to illustrate the relationship between the expressions of miRs-449a and -449b to retinoblastoma proliferation and apoptosis. We are the first to confirm an inhibitory effect of miR-449a and -449b in retinoblastoma by demonstrating significantly impaired proliferation and increased apoptosis of tumor cells when these miRNAs are overexpressed. This study suggests that these miRNAs could serve as viable therapeutic targets for retinoblastoma treatment.

Fernandes BF, Nikolitch K, Coates J, et al.
Local chemotherapeutic agents for the treatment of ocular malignancies.
Surv Ophthalmol. 2014 Jan-Feb; 59(1):97-114 [PubMed] Related Publications
We critically analyze available peer-reviewed literature, including clinical trials and case reports, on local ocular cancer treatments. Recent innovations in many areas of ocular oncology have introduced promising new therapies, but, for the most part, the optimal treatment of ocular malignancies remains elusive.

Chawla B, Jain A, Azad R
Conservative treatment modalities in retinoblastoma.
Indian J Ophthalmol. 2013; 61(9):479-85 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Retinoblastoma is the most common primary intraocular malignancy of childhood. A potentially curable cancer, its treatment has improved significantly over the last few decades. The purpose of this article is to review the literature on various conservative treatment modalities available for the treatment of retinoblastoma and their effectiveness, when used alone or in combination. Pubmed, Medline, Embase, and the Cochrane library were searched through 2012 for published peer reviewed data on conservative treatment modalities for retinoblastoma. Various studies show that while enucleation remains the standard of care for advanced intraocular tumors, conservative modalities that can result in globe salvage and preservation of useful vision are being increasingly employed. Such modalities include systemic chemotherapy, focal consolidation with transpupillary thermotherapy, laser photocoagulation and cryotherapy, plaque brachytherapy, and delivery of local chemotherapy using subconjunctival, sub-tenon, or intra-arterial routes. When used alone or in combination, these treatment modalities can help in avoidance of external beam radiotherapy or enucleation, thus reducing the potential for long-term side effects, while salvaging useful vision. Radioactive plaque brachytherapy has an established role in selected patients with intraocular retinoblastoma. Local injections of chemotherapeutic agents via the sub-tenon or sub-conjunctival route have been used with varying degrees of success, usually as an adjunct to systemic chemotherapy. Intra-arterial ophthalmic artery delivery of melphalan has shown promising results. It is important to recognize that today, several treatment options are available that can obviate the need for enucleation, and cure the cancer with preservation of functional vision. A thorough knowledge and understanding of these conservative treatment modalities is essential for appropriate management.

Villegas VM, Hess DJ, Wildner A, et al.
Curr Opin Ophthalmol. 2013; 24(6):581-8 [PubMed] Related Publications
PURPOSE OF REVIEW: Retinoblastoma is the most common malignant intraocular tumor of childhood. Treatment and diagnostic modalities associated to this condition are changing rapidly as our understanding of this condition crystallizes. The purpose of this review is to provide an update of the current understanding of retinoblastoma.
RECENT FINDINGS: Knowledge on tumorigenesis and genomic expression has expanded tremendously with the development of a mouse model for retinoblastoma. Tumor hypoxia has been identified as a significant step in the tumor progression and a novel target for future treatments. Current globe-sparing therapies, including periocular carboplatin, selective ophthalmic artery chemoreduction, intravitreal melphalan, and focal consolidation are being used and investigated actively. Diagnosis and the management of retinoblastoma is also undergoing major advances including wide-field photography, autofluorescence, and high-resolution optical coherence tomography.
SUMMARY: Progressive advances in the understanding of retinoblastoma pathogenesis continue to lead treatment strategies. Improvements in the diagnosis and management of retinoblastoma are improving morbidity and mortality associated to this condition in the developed nations. However, it is of outmost importance to flatten the international boundaries to offer prompt care to retinoblastoma children in underdeveloped communities.

Song HB, Jun HO, Kim JH, et al.
Anti-apoptotic effect of clusterin on cisplatin-induced cell death of retinoblastoma cells.
Oncol Rep. 2013; 30(6):2713-8 [PubMed] Related Publications
Clusterin is a cytoprotective chaperone protein that is known to protect various retinal cells. It was also reported to be overexpressed in several types of malignant tumors, whose chemoresistance correlates with the expression of clusterin. Herein, we investigated the effect of clusterin on cisplatin-induced cell death of retinoblastoma cells. Firstly, evaluation of clusterin expression demonstrated that it was highly expressed in human retinoblastoma tissues and cell lines (SNUOT-Rb1 and Y79) particularly in the area between viable cells around vessels and necrotic zones in the relatively avascular area in human retinoblastoma tissues. Furthermore, the effects of cisplatin on retinoblastoma cells were evaluated. Cisplatin (1 µg/ml) significantly affected cell viability of SNUOT-Rb1 cells by inducing caspase-3-dependent apoptosis. Notably, the cell death due to cisplatin was prevented by 5 µg/ml of clusterin administered 4 h prior to cisplatin treatment by inhibiting cisplatin-induced apoptosis. Furthermore, overexpression of clusterin exerted its anti-apoptotic effect on cisplatin-induced apoptosis, and effectively prevented cisplatin-induced cell death. These data suggest that clusterin, found to be expressed in human retinoblastoma, may exert anti-apoptotic effects on cisplatin-induced apoptosis and prevent cell death. Therefore, clusterin can contribute to cisplatin resistance of retinoblastoma.

Related: Apoptosis Cisplatin

Presley BC, Flannigan MJ
Emergency department bedside ultrasound diagnosis of retinoblastoma in a child.
Pediatr Emerg Care. 2013; 29(10):1128-31 [PubMed] Related Publications
A 30-month-old boy presented to a Haitian emergency department with proptosis, periorbital edema, and progressive blindness. Bedside ultrasound examination revealed bilateral ocular masses with dense calcifications pathognomonic for retinoblastoma. This case illustrates the diagnostic utility of bedside ultrasound for an advanced case of retinoblastoma in a resource-poor setting. Ocular ultrasound technique is also reviewed.

Related: Eye Cancer

Ryoo NK, Kim JE, Choung HK, et al.
Human papilloma virus in retinoblastoma tissues from Korean patients.
Korean J Ophthalmol. 2013; 27(5):368-71 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
PURPOSE: Recent reports suggest the association of human papilloma virus (HPV) with retinoblastoma. This study was performed to elucidate whether HPV infection is related to retinoblastoma among Koreans.
METHODS: A total of 54 cases diagnosed with retinoblastoma were enrolled from Seoul National University Children's Hospital and Seoul Metropolitan Government-Seoul National University Boramae Medical Center. Presence of human papilloma viral DNA was detected by in situ hybridization in formalin-fixed paraffin-embedded retinoblastoma tissues using both probes against high- and low risk HPV types.
RESULTS: The mean age at diagnosis was 22.0 months (range, 1.1 to 98.0 months), and the mean age at enucleation was 27.8 months (range, 1.5 to 112.7 months) among the 54 patients with retinoblastoma. HPV was not detected in any of the retinoblastoma samples using either high risk or low risk HPV probes.
CONCLUSIONS: Our study, being the first study in the Korean population, proposes that HPV infection may have no causal relationship with retinoblastoma in Koreans.

Choi YJ, Park C, Jin HC, et al.
Outcome of smooth surface tunnel porous polyethylene orbital implants (Medpor SST) in children with retinoblastoma.
Br J Ophthalmol. 2013; 97(12):1530-3 [PubMed] Related Publications
AIM: To evaluate the surgical outcome after the insertion of smooth surface tunnel porous polyethylene orbital implants (Medpor SST) in children with retinoblastoma.
METHODS: 44 consecutive children with retinoblastoma who underwent primary enucleation and Medpor SST implantation at Seoul National University Hospital from November 2004 to August 2009, with at least 24 months of follow-up were included. A retrospective review of cases was performed.
RESULTS: Mean age at the time of surgery was 24.7 months (range 1-65 months). The diameter of the spherical implant was 20 mm in 36 patients (81.8%) and 18 mm in 8 patients (18.2%). During a mean follow-up period of 60.1 months (range 26-93 months), there were no cases of implant exposure, extrusion or infection. Transient conjunctival thinning developed in three patients, but all resolved with conservative treatment. Anophthalmic socket complications such as lower lid malposition (retraction or entropion) (n=10, 22.7%), blepharoptosis (n=8, 18.2%) and enophthalmos (n=2, 4.5%) developed, but most showed acceptable cosmesis.
CONCLUSIONS: Medpor SST is relatively safe, allowing for a mean follow-up of 5 years in terms of implant exposure, and may be a good choice of orbital implant for children with retinoblastoma.

Mabtum ED, Bonanomi MT, Lima PP, Almeida MT
Orbital retinoblastoma: case report.
Arq Bras Oftalmol. 2013 Jul-Aug; 76(4):247-9 [PubMed] Related Publications
We describe the case of a 9-month old boy with unilateral retinoblastoma and bulftalmo. Primary enucleation was the treatment of choice due to the lack of visual prognosis. The histology of the enucleated eye showed massive choroidal invasion by the tumor and the optic nerve free of neoplastic tissue. Therefore, no adjuvant chemotherapy or radiotherapy was indicated. Three months after the enucleation, the patient returned with massive orbital retinoblastoma with exposure of the conjunctiva. Treated with chemotherapy, the patient has been in remission for 12 months. The risk factors for orbital recurrence are discussed.

Zafar SN, Ahmad SQ, Zafar N
Retinoblastoma in an adult.
BMC Res Notes. 2013; 6:304 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
BACKGROUND: Retinoblastoma is the most common pediatric ocular tumour. It may rarely present in adults. The present case adds to the number of 26 cases already published in literature since 1919 till 2013. Our aim is to highlight the rare occurrence of retinoblastoma in adults along with its features which differentiate it from paediatric retinoblastoma.
CASE PRESENTATION: We describe a case of adult onset retinoblastoma (group E, according to the international classification of retinoblastoma) occurring in a 25 year old male. He presented with decreasing visual acuity in the right eye of 4 months duration. He had neo-vascular glaucoma and pseudohypopyon. B scan ultrsonography of his right eye showed intraocular growth without any calcification. The CT scan of the orbits and brain showed intraocular growth in the right eye with no calcification. Enucleation of the right eye was carried out. Retinoblastoma was confirmed on histopathology of the enuleated globe.
CONCLUSIONS: The present case adds to the number of adult Rb patients reported in literature. Early detection to salvage the life can be made possible if the clinician keeps a high index of suspicion when observing retinal mass of adult onset. Proper counselling of the patient in order to seek his full involvement in management may help in improving the prognosis of the disease.

Carvalho IN, Reis AH, Cabello PH, Vargas FR
Polymorphisms of CDKN1A gene and risk of retinoblastoma.
Carcinogenesis. 2013; 34(12):2774-7 [PubMed] Related Publications
Retinoblastoma (RB) is a malignant neoplasia that occurs mostly in children under 5 years. Recently, CDKN1A gene has been shown to be up-regulated in a context of loss of function of pRb. This gene encodes the p21 protein, which is the bona fide effector of p53. We hypothesized whether two putatively functional single nucleotide polymorphisms (SNPs) of CDKN1A (rs1801270 C>A and rs1059234 C>T) may influence the risk and/or survival of RB patients. We genotyped both SNPs in 141 RB patients and 120 unrelated healthy individuals. Statistical analyses consisted of chi-square (χ(2)), odds ratio (OR) and survival curves by Kaplan-Meier method. We found that patients who carry the genotype CA for rs1801270 and CT for rs1059234 were associated to an increased risk of RB [OR = 2.5, 95% confidence interval (CI) = 1.38-4.53], whereas patients with CC for both polymorphisms were associated to a lower risk of developing RB (OR = 0.43, 95% CI = 0.25-0.74). On the other hand, Kaplan-Meier curves did not show statistically significant differences in survival among the studied polymorphisms. We conclude that the minor alleles of rs1801270 and rs1059234 polymorphisms may act as risk factors for the development of RB in our sample. Summary: The minor alleles of polymorphisms rs1801270 C>A and rs1059234 C>T in CDKN1A (p21) gene may act as risk factors for the development of RB; however, they do not seem to influence overall survival.

Related: CDKN1A

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