A Multicenter, International Collaborative Study for American Joint Committee on Cancer Staging of Retinoblastoma: Part I: Metastasis-Associated Mortality.

PURPOSE: To evaluate the ability of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to estimate metastatic and mortality rates for children with retinoblastoma (RB). DESIGN: International, multicenter, registry-based retrospective case series. PARTICIPANTS: A total of 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. METHODS: Patient-specific data fields for RB were designed and selected by subcommittee. All patients with RB with adequate records to allow tumor staging by the AJCC criteria and follow-up for metastatic disease were studied. MAIN OUTCOME MEASURES: Metastasis-related 5- and 10-year survival data after initial tumor staging were estimated with the Kaplan-Meier method depending on AJCC clinical (cTNM) and pathological (pTNM) tumor, node, metastasis category and age, tumor laterality, and presence of heritable trait. RESULTS: Of 2190 patients, the records of 2085 patients (95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. A total of 1260 patients (65.4%) had unilateral RB. Among the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b in 168 (8.1%), cT2a in 197 (9.4%), cT2b in 812 (38.9%), cT3 in 835 (40.0%), and cT4 in 18 (0.9%). Of these, 1397 eyes in 1353 patients (48.1%) were treated with enucleation. A total of 109 patients (5.2%) developed metastases and died. The median time (n = 92) from diagnosis to metastasis was 9.50 months. The 5-year Kaplan-Meier cumulative survival estimates by clinical tumor categories were 100% for category cT1a, 98% (95% confidence interval [CI], 97-99) for cT1b and cT2a, 96% (95% CI, 95-97) for cT2b, 89% (95% CI, 88-90) for cT3 tumors, and 45% (95% CI, 31-59) for cT4 tumors. Risk of metastasis increased with increasing cT (and pT) category (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastasis in category cT3 (hazard rate [HR], 8.09; 95% CI, 2.55-25.70; P < 0.001) and cT4 (HR, 48.55; 95% CI, 12.86-183.27; P < 0.001) compared with category cT1. Age, tumor laterality, and presence of heritable traits did not influence the incidence of metastatic disease. CONCLUSIONS: Multicenter, international, internet-based data sharing facilitated analysis of the 8th edition AJCC RB Staging System for metastasis-related mortality and offered a proof of concept yielding quantitative, predictive estimates per category in a large, real-life, heterogeneous patient population with RB.

High-Risk Histopathology Features in Primary and Secondary Enucleated International Intraocular Retinoblastoma Classification Group D Eyes.

PURPOSE: To evaluate the rate and identify the risk factors for high-risk histopathologic features in group D retinoblastoma eyes enucleated as primary or secondary treatment. DESIGN: Retrospective analysis. PARTICIPANTS: A total of 64 enucleated group D eyes (62 patients), of which 40 (40 patients) were primary and 24 (22 patients) were secondary to other treatments. METHODS: Clinicopathologic correlation of consecutive group D eyes enucleated from 2002 to 2014. High-risk histopathologic features were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body/muscle infiltration, massive (≥3 mm) choroidal invasion, retrolaminar optic nerve invasion, or combined non-massive choroidal and prelaminar/laminar optic nerve invasion. MAIN OUTCOME MEASURES: High-risk histopathologic features, metastasis, and death. RESULTS: Of the 64 group D eyes, 37 (58%) were classified as cT2bN0M0H0, 24 (38%) were classified as cT2bN0M0H1, and 3 (5%) were classified as cT2aN0M0H1, according to the 8th edition cTNMH Retinoblastoma Staging. High-risk histopathologic features were detected in 10 eyes (16%) in the entire cohort, 5 eyes (13%) of the primary enucleated group (pT3aNxM0, n = 2 and pT3bNxM0, n = 3, 8th edition pTNM), and 5 eyes (21%) of the secondary enucleated group (pT2bNxM0, n = 2, pT3aNxM0, n = 2 and pT3cNxM0, n = 1). Absence of vitreous seeds at presentation was the only predictive factor found for high-risk histopathologic features in the primary enucleation group (P = 0.042), whereas none were found in the secondary group (P ≥ 0.179). Invasion of the anterior structures (anterior chamber, iris, ciliary body/muscle) was detected significantly more after secondary enucleation (P = 0.048). All patients with high-risk histopathologic features were treated with adjuvant chemotherapy, and no metastases were recorded in a median follow-up time of 73.2 months (mean, 71.5; range, 13.7-153.0). CONCLUSIONS: The choice of primary treatment for group D retinoblastoma should be carefully weighed, because according to this study, 13% of eyes harbor high-risk histopathologic features at presentation, with the absence of vitreous seeds being a potential risk factor. It is of special importance in group D eyes being considered for nonsystemic treatment, such as primary intraophthalmic artery chemotherapy. Secondary enucleated group D eyes with high-risk histopathologic features more commonly involved anterior structures, warranting meticulous clinical and histologic examinations for this subset of patients.

Vitreous Seeds in Retinoblastoma: Clinicopathologic Classification and Correlation.

PURPOSE: A recent classification scheme for retinoblastoma vitreous seeds has shown promise in predicting treatment response. For the first time, we correlate this clinical classification scheme with its histopathologic features. DESIGN: Retrospective review. PARTICIPANTS: Enucleated eyes received at the pathology department of the Retinoblastoma Center of Houston from 2010 to 2015. METHODS: Macroscopic photographs of the enucleated eyes of patients with retinoblastoma were analyzed to select those with vitreous seeds. Cases with adequate material for clinicopathologic correlation were selected for further analysis, and clinical photographs were reviewed. Routine histopathologic slides were reviewed and compared with the clinical and macroscopic photographs. Seeds were classified as type 1 ("dust"), type 2 ("sphere"), or type 3 ("cloud"). To confirm the presence of macrophages, CD68 immunohistochemical staining was used. Synaptophysin was used to stain retinoblastoma cells. MAIN OUTCOME MEASURES: To correlate clinical vitreous seed type with histopathologic features. RESULTS: A total of 14 eyes with adequate amounts of tumor seeds along with clinical and macroscopic photographic correlation were selected from a total of 138 eyes reviewed. Type 1 seeds consisted of individual viable tumor cells and scattered macrophages. Type 2 seeds consisted of 2 submorphologies: spheres with viable cells throughout and spheres with an outer rim of viable cells but necrotic cells centrally. Type 3 seeds were composed of more than 90% necrotic material admixed with few macrophages and viable cells at their outer rim. Untreated (8/14) and previously treated (6/14) eyes showed similar histopathologic features for each type of seeds. Treated eyes had more type 1 and 3 seeds. CONCLUSIONS: We provide the first histopathologic correlation of the clinical classification scheme for vitreous seeds in retinoblastoma. "Dust" is formed by scattered single cells alternating with macrophages. "Spheres" with translucent centers contain multiple layers of viable tumor cells that shed single cells and may be more clinically aggressive. "Cloud" seeds are mostly composed of necrotic material, explaining their lack of therapeutic response. Pretreated eyes showed tumor seeds morphologically similar to untreated eyes. Knowledge of the underlying histopathology of vitreous seed types is a fundamental component of classification and may aid in understanding clinical response to treatment.

Long-term outcomes of Group D retinoblastoma eyes during the intravitreal melphalan era.

BACKGROUND: To evaluate outcomes of Group D retinoblastoma (Rb) eyes during the intravitreal melphalan era. PROCEDURE: Retrospective chart review of patients diagnosed with Group D Rb from 2011 to 2016 was done. Overall, 76 Group D eyes of 68 patients were included; salvage therapy included systemic chemoreduction with vincristine, etoposide, and carboplatin with local consolidation, followed by intravitreal injection of melphalan for recurrent or persistent seeding. External beam radiation was not used as a treatment modality. Primary outcome measurement was globe salvage. RESULTS: Of 76 Group D eyes, 24 were enucleated primarily and 52 were treated with intent to salvage the globe. Systemic chemoreduction salvaged 25 of 52 eyes (48%). Tumor recurrences were diagnosed in 27 eyes (52%); five with massive retinal recurrences underwent enucleation and 22 were treated with intravitreal melphalan injection. Of the 22 injected eyes, 14 (64%) were salvaged and eight required enucleation primarily for retinal recurrences. Success in eradicating vitreous seeds was 100%. The Kaplan-Meier 3-year survival estimate for treated eyes is 76.5% (95% CI: 61.4-86.3). Median follow-up for the group of 76 Group D eyes was 29.5 months (SD 17.9 months). CONCLUSION: During a 6-year period that included the initiation of intravitreal melphalan at our institution, the salvage rate of treated Group D eyes was 75% (39/52 eyes). Intravitreal melphalan was utilized for ocular salvage in 42% (22/52 eyes). Systemic chemoreduction combined with intravitreal melphalan for seeding demonstrated a high overall salvage rate for Group D eyes in this cohort.

Favorable outcome of alternate systemic and intra-arterial chemotherapy for retinoblastoma.

The recent trend of treatment for retinoblastoma is to salvage the eye globes as well as achieving patients' survival. Intra-arterial chemotherapy (IAC) is one of the current standard treatment; however, it cannot exclude the risk of occult micrometastases in the central nervous system in advanced-stage retinoblastoma. Alternate fashion of intravenous chemotherapy (IVC) and IAC strategy was developed to increase the eye salvage rate and to reduce the metastatic risk. Between January 2012 and December 2014, 13 eyes of 12 patients with newly diagnosed retinoblastoma received alternate chemotherapy using IVC and IAC in Yonsei Cancer Center. Eye salvage rate was assessed by the eye preservation time, which was defined as the duration from the diagnosis to the time of enucleation. Total 13 eyes were classified according to the International Classification of Retinoblastoma (ICRB) as group B (n = 1, 7.7%), group C (n = 2, 15.4%), group D (n = 5, 38.5%), or group E (n = 5, 38.5%). IAC was performed, 3 to 5 times (median: 4 times) for each eye, total 54 times. Five to 15 courses (median: 8 courses) of systemic chemotherapy were performed in the patients. During the median follow-up period of 30.4 months, overall eye salvage rate was 63.9 ± 14.7%. All patients survived. The treatment was tolerable without significant complications. These results showed that primary alternate IVC-IAC was tolerable and effective for retinoblastoma.

The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan.

PURPOSE: To evaluate the clinical characteristics of the 3 classifications of vitreous seeds in retinoblastoma-dust (class 1), spheres (class 2), and clouds (class 3)-and their responses to intravitreal melphalan. DESIGN: Retrospective, bi-institutional cohort study. PARTICIPANTS: A total of 87 patient eyes received 475 intravitreal injections of melphalan (median dose, 30 µg) given weekly, a median of 5 times (range, 1-12 times). METHODS: At presentation, the vitreous seeds were classified into 3 groups: dust, spheres, and clouds. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to evaluate clinical response to weekly intravitreal melphalan injections and time to regression of vitreous seeds. Kaplan-Meier estimates of time to regression and ocular survival, patient survival, and event-free survival (EFS) were calculated and then compared using the Mantel-Cox test of curve. MAIN OUTCOME MEASURES: Time to regression of vitreous seeds, patient survival, ocular survival, and EFS. RESULTS: The difference in time to regression was significantly different for the 3 seed classes (P < 0.0001): the median time to regression was 0.6, 1.7, and 7.7 months for dust, spheres, and clouds, respectively. Eyes with dust received significantly fewer injections and a lower median and cumulative dose of melphalan, whereas eyes with clouds received significantly more injections and a higher median and cumulative dose of melphalan. Overall, the 2-year Kaplan-Meier estimates for ocular survival, patient survival, and EFS (related to target seeds) were 90.4% (95% confidence interval [CI], 79.7-95.6), 100%, and 98.5% (95% CI, 90-99.7), respectively. CONCLUSIONS: The regression and response of vitreous seeds to intravitreal melphalan are different for each seed classification. The vitreous seed classification can be predictive of time to regression, number, median dose, and cumulative dose of intravitreal melphalan injections required.

PREDICTIVE VALUE OF TNM CLASSIFICATION, INTERNATIONAL CLASSIFICATION, AND REESE-ELLSWORTH STAGING OF RETINOBLASTOMA FOR THE LIKELIHOOD OF HIGH-RISK PATHOLOGIC FEATURES.

PURPOSE: To evaluate the predictive value of the seventh edition American Joint Committee on Cancer (AJCC/UICC) TNM classification, the International Classification of Retinoblastoma (ICRB), and Reese-Ellsworth staging for retinoblastoma for the likelihood of high-risk pathologic features. METHODS: A retrospective study of 50 primarily enucleated eyes from 49 retinoblastoma patients. Main outcome measures included demographics, TNM stage, ICRB group, Reese-Ellsworth stage, choroid, optic nerve, and anterior chamber invasion. RESULTS: The median age at enucleation was 30 months. High-risk pathologic features mandating adjuvant chemotherapy were seen in 5 of T2 eyes (22%), in 15 of T3 eyes (56%) (P = 0.021), in 1 of ICRB Group C eyes (13%), 8 of Group D eyes (33%), and 11 of Group E eyes (61%) (P = 0.035). High-risk pathologic features were 4.61 and 3.68 times more likely to be diagnosed at a more advanced T stage and ICRB group consecutively, whereas 0.133 time less likely to be diagnosed at a more advanced Reese-Ellsworth stage. At median follow-up of 40 months, no single case had metastasis or was dead. CONCLUSION: The higher tumor clinical TNM stage and the more advanced ICRB group at presentation are associated with higher frequency of high-risk pathologic features and may predict which patients should receive adjuvant chemotherapy.

Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma.

OBJECTIVE: To analyze our 5-year experience of intra-arterial chemotherapy (IAC) for retinoblastoma as primary or secondary therapy. DESIGN: Retrospective interventional case series. PARTICIPANTS: A total of 70 eyes of 67 patients. INTERVENTION: Ophthalmic artery chemotherapy infusion under fluoroscopic guidance was performed using melphalan (3, 5, or 7.5 mg) in every case, with additional topotecan (1 mg) and/or carboplatin (30 or 50 mg) as necessary. MAIN OUTCOME MEASURES: Tumor control and treatment complications. RESULTS: The mean patient age at IAC was 30 months. The treatment was primary in 36 eyes and secondary in 34 eyes. Those primary therapy eyes were classified according to the International Classification of Retinoblastoma (ICRB) as group A (n = 0), B (n = 1), C (n = 4), D (n = 17), or E (n = 14). The secondary therapy eyes had failed previous intravenous chemotherapy (n = 34) in every case. Each eye received a mean of 3 IAC sessions per eye (median, 3; range, 1-7 sessions). After IAC with a mean follow-up of 19 months, globe salvage was achieved in 72% of primary-treated cases and in 62% of secondary-treated cases. Specifically, primary therapy achieved globe salvage for group B (100%), group C (100%), group D (94%), and group E (36%). Of all 70 eyes, complete regression was achieved for solid tumor in 48 of 51 eyes (94%), subretinal seeds in 40 of 42 eyes (95%), and vitreous seeds in 34 of 39 eyes (87%). After each catheterization (n = 198), the main complications included transient eyelid edema (5%), blepharoptosis (5%), and forehead hyperemia (2%). More lasting complications included vitreous hemorrhage (2%), branch retinal artery obstruction (1%), ophthalmic artery spasm with reperfusion (2%), ophthalmic artery obstruction (2%), partial choroidal ischemia (2%), and optic neuropathy (<1%). Over the past 3 years, the combined incidence of ophthalmic, retinal, and choroidal vascular ischemia was reduced to 1%. There was no patient with stroke, seizure, neurologic impairment, limb ischemia, secondary leukemia, metastasis, or death. CONCLUSIONS: Five-year experience with IAC indicates that this technique is remarkably effective for the management of retinoblastoma as both a primary and a secondary treatment.

Gene expression profiling identifies different sub-types of retinoblastoma.

BACKGROUND: Mutation of the RB1 gene is necessary but not sufficient for the development of retinoblastoma. The nature of events occurring subsequent to RB1 mutation is unclear, as is the retinal cell-of-origin of this tumour. METHODS: Gene expression profiling of 21 retinoblastomas was carried out to identify genetic events that contribute to tumorigenesis and to obtain information about tumour histogenesis. RESULTS: Expression analysis showed a clear separation of retinoblastomas into two groups. Group 1 retinoblastomas express genes associated with a range of different retinal cell types, suggesting derivation from a retinal progenitor cell type. Recurrent chromosomal alterations typical of retinoblastoma, for example, chromosome 1q and 6p gain and 16q loss were also a feature of this group, and clinically they were characterised by an invasive pattern of tumour growth. In contrast, group 2 retinoblastomas were found to retain many characteristics of cone photoreceptor cells and appear to exploit the high metabolic capacity of this cell type in order to promote tumour proliferation. CONCLUSION: Retinoblastoma is a heterogeneous tumour with variable biology and clinical characteristics.

High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes.

PURPOSE: To determine the correlation between the International Classification of Retinoblastoma (ICRB) and histopathologic high-risk retinoblastoma. DESIGN: Retrospective study. PARTICIPANTS: A total of 519 patients. INTERVENTION: Primary enucleation. MAIN OUTCOME MEASURES: High-risk retinoblastoma, metastasis, and death. RESULTS: Of 519 primarily enucleated eyes, 87 (17%) were classified as group D and 432 (83%) were classified as group E on the basis of the ICRB. High-risk retinoblastoma was identified in 23% (117/519) of enucleated eyes, including 17% (15/87) group D and 24% (102/432) group E eyes. High-risk histopathologic features of retinoblastoma included anterior chamber involvement (5/15 [33%] group D eyes, 31/102 [30%] group E eyes), isolated massive posterior uveal invasion ≥ 3 mm (7/15 [47%] group D eyes, 22/102 [22%] group E eyes), isolated post-laminar optic nerve invasion (2/15 [13%] group D eyes, 46/102 [45%] group E eyes), and any combination of posterior uveal invasion and optic nerve involvement (7/15 [47%] group D eyes, 37/102 [36%] group E eyes). On logistic regression analysis, massive posterior uveal invasion ≥ 3 mm was more common in group D eyes (P = 0.0442), and post-laminar optic nerve invasion was more common in group E eyes (P = 0.0390). Of 117 patients with high-risk retinoblastoma, systemic adjuvant chemotherapy was administered in 83 patients (71%). Systemic metastasis developed in 0% (0/15) of those with high-risk group D retinoblastoma and 10% (10/102) of those with high-risk group E retinoblastoma over a mean follow-up period of 78 months (median, 62 months; range, 1-419 months). There was no metastasis in any patient (n = 402) classified with non-high-risk retinoblastoma. Of the 10 patients who developed metastasis, 4 had received prior adjuvant chemotherapy and 6 had no prior adjuvant chemotherapy. There was no metastasis in high-risk patients treated with vincristine sulphate, etoposide phosphate, and carboplatin (VEC). Death from metastasis occurred in 4% of high-risk patients (5/117). CONCLUSIONS: On the basis of the ICRB, 17% of group D and 24% of group E eyes are at increased risk for metastatic disease. In this study, 8% of patients developed metastasis. There was no metastasis in any patient classified with non-high-risk retinoblastoma. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression.

Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of earlier onset, includes most of the heritable forms. It harbors few genetic alterations other than the initiating RB1 inactivation and corresponds to differentiated tumors expressing mature cone markers. By contrast, subtype 2 tumors harbor frequent recurrent genetic alterations including MYCN-amplification. They express markers of less differentiated cone together with neuronal/ganglion cell markers with marked inter- and intra-tumor heterogeneity. The cone dedifferentiation in subtype 2 is associated with stemness features including low immune and interferon response, E2F and MYC/MYCN activation and a higher propensity for metastasis. The recognition of these two subtypes, one maintaining a cone-differentiated state, and the other, more aggressive, associated with cone dedifferentiation and expression of neuronal markers, opens up important biological and clinical perspectives for retinoblastomas.

Tumour size criteria for Group D and E eyes in the International Classification System for Retinoblastoma: effects on rates of globe salvage and high-risk histopathologic features.

PURPOSE: To determine the significance of large tumour size as a criteria for classifying advanced intraocular retinoblastoma, analysing rates of globe survival and high-risk (HE) histopathologic features. METHODS: Retrospective chart review of 212 eyes diagnosed with Group D (111 eyes) or Group E (101 eyes) retinoblastoma in at least one eye from January 1, 2006 to December 31, 2016 using the Los Angeles (LA) Classification System (no tumour size criteria for Group E). The 111 Group D tumours were then reclassified to Group E using 10, 12, 14, 16, 18 mm tumour size criteria, as determined by ultrasound or magnetic resonance imaging dimensions. RESULTS: For eyes in the original LA classification, 66.7% of Group D and 10.5% of Group E eyes undergoing globe preservation therapy avoided enucleation or radiotherapy (p < 0.0001; median follow-up of 33.0 months). In the LA classification, 8.5% of Group D and 26.3% of Group E enucleated globes had HE histopathologic features (p = 0.0065). When Group D eyes with tumours meeting the size criteria were reclassified to Group E, 65.7-74.4% of Group D and 16.1-36.7% of Group E eyes avoided enucleation or radiotherapy. Applying the tumour size criteria, 0-10.9% of Group D and 20.7-23.8% of Group E eyes had HE histopathologic features. CONCLUSION: Our retrospective analysis suggests that a large tumour size criteria for Group E retinoblastoma have no clinical basis, given that the LA classification system provided the greatest separation in globe salvage rates between Group D and E eyes. The LA classification system was also able to show a statistically significant difference in the rates of HE histopathologic features between Group D and E eyes. To avoid discrepancies in the literature, we recommend that centres use one uniform system for classifying advanced intraocular retinoblastoma.

Chemoreduction for group E retinoblastoma: comparison of chemoreduction alone versus chemoreduction plus low-dose external radiotherapy in 76 eyes.

PURPOSE: To evaluate chemoreduction (CRD) for group E retinoblastoma. DESIGN: Retrospective, comparative case series. PARTICIPANTS: Seventy-six eyes of 56 patients with group E retinoblastoma were treated with CRD alone or CRD plus low-dose prophylactic external beam radiotherapy (CRD+P-EBR). The CRD included vincristine, etoposide, and carboplatin (6 cycles). The P-EBR was given routinely 2 months after completion of CRD at a suggested dose of 2600 cGy. Therapeutic EBR (T-EBR) was only given at the time of extensive tumor recurrence at a suggested dose of 3800 cGy. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Globe salvage. RESULTS: Of the 76 eyes, 64 received CRD alone and 12 received CRD+P-EBR. At the 2-year follow-up, globe salvage was achieved in 29 (53%) of 55 eyes in the CRD group and in 10 (91%) of 11 eyes in the CRD+P-EBR group. At 5 years, globe salvage was achieved in 20 (48%) of 42 eyes in the CRD group and in 4 (80%) of 5 eyes in the CRD+P-EBR group (P=0.347). Of the 64 eyes in the CRD group, 16 (25%) were salvaged with CRD alone and 13 (20%) with CRD+T-EBR, whereas 22 (34%) were enucleated after CRD alone and 13 (20%) were enucleated after CRD+T-EBR. Of the 12 eyes in the CRD+P-EBR group, 10 (83%) were salvaged with CRD+P-EBR, whereas 2 (17%) were enucleated and none required T-EBR. The median dose for T-EBR was 3800 cGy, and that for P-EBR was 2600 cGy. Eyes treated with CRD+P-EBR showed significantly less recurrence, leading to less chance of enucleation or therapeutic radiotherapy than that for CRD alone (P<0.001). Visual acuity was 20/100 or better or fix and follow in 9 (32%) of 28 salvaged eyes in the CRD group and in 4 (40%) of 10 in the CRD+P-EBR group. At 5 years, there were no patients in either group with metastasis of pinealoblastoma or who had died. In one patient in the CRD group, a second cancer developed. CONCLUSIONS: Group E retinoblastoma managed with CRD+P-EBR showed significantly less need for enucleation or therapeutic radiotherapy than eyes treated with CRD alone. These findings merit further study and consideration.

Retinoblastoma for Pediatric Ophthalmologists.

Retinoblastoma can present in 1 or both eyes and is the most common intraocular malignancy in childhood. It is typically initiated by biallelic mutation of the RB1 tumor suppressor gene, leading to malignant transformation of primitive retinal cells. The most common presentation is leukocoria, followed by strabismus. Heritable retinoblastoma accounts for 45% of all cases, with 80% being bilateral. Treatment and prognosis of retinoblastoma is dictated by the disease stage at initial presentation. The 8th Edition American Joint Committee on Cancer (AJCC) TNMH (tumor, node, metastasis, heritable trait) staging system defines evidence-based clinical and pathological staging for overall prognosis for eye(s) and child. Multiple treatment options are available in 2018 for retinoblastoma management with a multidisciplinary team, including pediatric ocular oncology, medical oncology, radiation oncology, genetics, nursing, and social work. Survival exceeds 95% when disease is diagnosed early and treated in centers specializing in retinoblastoma. However, survival rates are less than 50% with extraocular tumor dissemination. We summarize the epidemiology, genetics, prenatal screening, diagnosis, classification, investigations, and current therapeutic options in the management of retinoblastoma.

The National Registry of Retinoblastoma in Japan (1983-2014).

PURPOSE: To review the clinical findings of retinoblastoma recorded over a period of 32 years by the National Registry of Retinoblastoma in Japan. STUDY DESIGN: Retrospective. METHODS: We reviewed the diagnoses, clinical pictures, and treatment data recorded on a yearly basis from 1983 until 2014 by major Japanese medical facilities. RESULTS: A total of 2360 patients (1225 boys, 1135 girls) were analyzed. Of those, 67.3% had unilateral retinoblastoma, 32.7% had bilateral retinoblastoma, and 6.7% had a family history of retinoblastoma. The average occurrence frequency for retinoblastoma was 1:16,823 births/year. At diagnosis, 89.0% of the patients were aged younger than 3 years and 41.0% were aged younger than 1 year. The most common initial symptom was leukocoria (48.9%), which was followed by cat's eye (17.1%) and strabismus (14.8%). Of the total 3131 eyes, 53.0% were Reese-Ellsworth group V. As per the International Classification of Retinoblastoma, 33.7% of the eyes were group D, and 30.1% were group E. Enucleation was performed in 1545 eyes (52.2%), and subsequent treatment was administered in 379 eyes. Conservative therapy was performed in 1415 eyes (47.8%) of 926 patients. The number of eyes receiving conservative therapy increased every year, even in about 30% of those with advanced group V eyes. Radiation therapy was the primary conservative therapy before the year 2000 and was thereafter replaced by chemotherapy. In the eyes receiving chemotherapy, anticancer agents were administered systematically in one-third of the eyes, locally in another one-third of the eyes, or as a combination of both in the other one-third. Conservative therapy successfully preserved in over 90% of the eyes of groups I to IV and in 78.1% of the eyes of group V. CONCLUSIONS: Retinoblastoma is often diagnosed at an advanced stage. With the development of systemic and local chemotherapy, the number of eyes with advanced retinoblastoma preserved by conservative therapy has been increasing.

Current management strategies for intraocular retinoblastoma.

Survival rates for retinoblastoma patients have increased dramatically over the last century, with documented 5-year survival figures reaching 87-99% in developed countries. During the last decade, there has been a dramatic paradigm shift in the treatment approach for intraocular retinoblastoma, emphasising chemoreduction protocols and minimising the use of external beam radiation. The recognition of the increased risk for second non-ocular cancers with external beam radiation contributed to the growing emergence of chemotherapy. Although chemoreduction protocols vary slightly between institutions, many centres are currently treating intraocular retinoblastoma with carboplatin, vincristine and etoposide as a three-drug regimen given in two to six cycles. Clinical studies have demonstrated that systemic chemotherapy must be combined with other modalities, such as laser treatment and cryotherapy, for adequate tumour control and many eyes with advanced intraocular disease require salvage therapy with radiation or enucleation. Therefore, modern centres treating retinoblastoma continue to manage patients with a variety of modalities, individualising the therapy according to the patient's presentation and clinical course.

Lag time for retinoblastoma in the UK revisited: a retrospective analysis.

OBJECTIVES: To explore current delays in diagnosis of retinoblastoma (Rb) and effect on outcome with comparison to a study from the 1990s. SETTING: Primary, secondary, tertiary care: majority from South of England. PARTICIPANTS: A retrospective analysis of 93 new referrals of sporadic (non-familial) Rb to a specialist Rb unit in London, UK from January 2006 to February 2014. PRIMARY AND SECONDARY OUTCOMES: International Intraocular Retinoblastoma Classification, lag times including parental delay and healthcare professional delay, patients requiring enucleation and requirement of adjuvant chemotherapy postenucleation (high-risk Rb). RESULTS: During the study period, 29% presented via accident and emergency (A&E). The median referral time from symptom onset to visiting primary care (PC) was 28 days and PC to ophthalmologist 3 days (range 0-181 days). The median time from local ophthalmologist to the Rb Unit was 6 days (0-33). No significant correlation was found between delay and International Classification of Retinoblastoma grade (p>0.05) or between postenucleation adjuvant chemotherapy and enucleation groups (p>0.05). Less enucleations (60%) are being performed compared with the previous study (81%) (p=0.0015). CONCLUSIONS: Parents are attending A&E more compared with the 1990s and this may reflect the effect of public awareness campaigns. More eyes are being salvaged despite a similar number of children requiring adjuvant chemotherapy. High-risk Rb and Group E eyes do not correlate with increased lag time in the UK. Other determinants such as tumour biology may be more relevant.

The International Classification of Retinoblastoma predicts chemoreduction success.

PURPOSE: To evaluate the reliability of the International Classification of Retinoblastoma (ICRB) for predicting treatment success with chemoreduction (CRD). DESIGN: Noncomparative interventional case series. PARTICIPANTS: Two hundred forty-nine consecutive eyes. METHODS: All eyes were treated with CRD and were classified according to the ICRB: group A included those eyes with retinoblastoma 3 mm, macular location, or minor subretinal fluid; group C included those eyes with retinoblastoma with localized seeds; group D included those eyes with retinoblastoma with diffuse seeds; group E included those eyes with massive retinoblastoma necessitating enucleation. The CRD regimen included vincristine, etoposide, and carboplatin for 6 cycles plus local consolidation with thermotherapy or cryotherapy. MAIN OUTCOME MEASURE: Chemoreduction success, defined as avoidance of external beam radiotherapy or enucleation. RESULTS: Of the 249 eyes, 23 (9%) were in group A, 96 (39%) were in group B, 21 (8%) were in group C, and 109 (44%) were in group D. In this series, group E eyes were managed with enucleation. Treatment success was achieved in 100% of group A, 93% of group B, 90% of group C, and 47% of group D eyes. CONCLUSIONS: The ICRB can be of assistance in predicting CRD success for retinoblastoma. Additional treatment methods are necessary to salvage more group D eyes.