International Retinoblastoma Staging Research Articles

NEWLY DIAGNOSED ACTIVE RETINOBLASTOMA IN ADULTS.

To describe the clinical features, treatment, and outcome of retinoblastoma in adults. Retrospective case series. The mean age at initial presentation of retinoblastoma was 30 years (median, 26 years; range, 22-48 years). There were four males and four females, and all manifested unilateral retinoblastoma. The mean duration of symptoms was 22 months (median, 12 months; range, 1-100 months). Six patients had intraocular retinoblastoma, and 2 had secondary orbital involvement. The eyes with intraocular retinoblastoma were classified according to the International Classification of Retinoblastoma as Group D (n = 3) or Group E (n = 3). The primary treatment for intraocular retinoblastoma (n = 6) included systemic chemotherapy (n = 1), external beam radiotherapy (n = 2), and enucleation (n = 3). Secondary treatment for tumor recurrence included enucleation (n = 2), and combination of intraarterial chemotherapy, intravitreal chemotherapy, and plaque radiotherapy (n = 1). The eyes with orbital extension of retinoblastoma were classified according to the International Retinoblastoma Staging System as Stage 3a (n = 2). The primary treatment for those with orbital extension of retinoblastoma included multimodality treatment (combination of systemic chemotherapy, orbital exenteration, and external beam radiotherapy). Systemic metastasis and related death occurred in one case. Retinoblastoma in adults is uncommon. Active tumor in this age group is usually advanced, necessitating enucleation and/or orbital exenteration.

Sirtuin1 Expression and Correlation with Histopathological Features in Retinoblastoma

Background: Sirtuin1 (Sirt1) is a member of highly conserved proteins and has been implicated as a tumor promoter as well as a tumor suppressor. One of the mechanisms involves deacetylation of retinoblastoma protein, thereby inhibiting the tumor suppressor function. No study has been reported on the expression of Sirt1 in retinoblastoma. Methods: We assessed the expression of Sirt1 in sections of archived tissue blocks of enucleated and exenterated specimens of retinoblastoma patients by immunohistochemistry. The histopathological features were reviewed and correlated with the expression of Sirt1. The effect of Sirt1 expression on survival was also assessed. Results: Retrospective data of 94 patients revealed that the median age at presentation was 36 months, with a male:female ratio of 1.9:1. Fifty-one percent of the patients had International Retinoblastoma Staging System (IRSS) stage 1 disease. Of the 94 sections, 89 (95%) expressed Sirt1. Forty-eight percent of the specimens showed grade 3 staining (>75% of the cells), and the intensity was 3+ in 53%. No association between Sirt1 expression and any histopathological feature was noted. Further, Sirt1 expression did not affect the overall and progression-free survival. Conclusions: Sirt1 was expressed in most of the retinoblastoma samples. However, the degree of Sirt1 expression was not associated with any high-risk histopathological feature or survival.

Retinoblastoma.

Retinoblastoma is the most common primary intraocular malignancy of childhood. It typically presents with leukocoria or strabismus. In later stages of the disease, the child may exhibit proptosis, buphthalmos, or hypopyon. The pathognomonic molecular aberration is a loss of function mutation in the RB1 gene on chromosome 13q. The degree of tumor involvement within the eye is defined by its group. Grouping was historically done with Reese-Ellsworth System. Recent therapeutic advances have led to the development of a new grouping system, the International Classification of Retinoblastoma (ICRB). In cases of extraocular extension and metastatic disease, the degree of tumor involvement outside of the eye is defined by its stage. Retinoblastoma is staged using the International Retinoblastoma Staging System (IRSS). Children with intraocular retinoblastoma have an excellent overall and ocular survival. In order to avoid the morbidity of enucleation and external beam radiation, treatments for isolated intraocular retinoblastoma have progressively moved toward targeted local modalities. Patients with extraocular involvement, such as those with trilateral retinoblastoma, have a poorer prognosis. The majority of these higher stage patients are now able to be cured with combination chemotherapy.

Retinoblastoma: An institutional experience

Background: This article aims to describe histopathologic high risk tumor characteristics in our patient population of retinoblastoma. It is based on consensus criteria for definitions of choroidal and optic nerve invasion as outlined in The International RetinoblastomaStaging Working Group (IRSWG) 2009.Materials and Methods: Fifty histopathologically diagnosed cases of retinoblastoma were archived from records of Pathology department during years 2004 to 2014. Re-evaluation of slides to identify choroidal and optic nerve invasion as per IRSWG along with Pathologic tumor staging was done. Data were entered into Microsoft excel sheets and results expressed in percentages. Department of Ophthalmology was consulted for recurrence of Retinoblastoma.Results: Among fifty cases, Choroidal invasion was absent in 62% cases. Minimal invasion (<3mm) was seen in 18% cases, massive (>3mm) in 14% cases and extra ocular involvement in 6% cases. The optic nerve was free of tumor in more than three forth of the cases (78%). Prelaminar and retro laminar involvement of optic nerve was observed in 6% and 10% cases respectively. Intraocular spread of tumor was observed in 6% of cases. The cut margin of optic nerve was involved in 42% while it was free of tumor in 58% of cases. Significant number of tumours were pathologically classified as pT1 (58%) followed by pT2a (22%). pT3a and pT4b were found in 6% each and pT3b and pT4a were found in 4% each. Recurrence was observed in two cases of PT3a and one of pT4b.Conclusion: We conclude identifying low percentages of high risk charateristics in a retrospective histologic experience with Retinoblastoma. Recurrence observed in two tumours staged pT3a sheds light on prognostic significance of reporting massive choroidal invasion despite free cut margin. These observations call for routine practice of standardized histopathologic reporting and processing of enucleated eye samples at our tertiary care centre.Journal of Pathology of Nepal (2015) Vol. 5, 723-726

Assessment of early-stage optic nerve invasion in retinoblastoma using high-resolution 1.5 Tesla MRI with surface coils: a multicentre, prospective accuracy study with histopathological correlation.

To assess the accuracy of high-resolution (HR) magnetic resonance imaging (MRI) in diagnosing early-stage optic nerve (ON) invasion in a retinoblastoma cohort. This IRB-approved, prospective multicenter study included 95 patients (55 boys, 40 girls; mean age, 29 months). 1.5-T MRI was performed using surface coils before enucleation, including spin-echo unenhanced and contrast-enhanced (CE) T1-weighted sequences (slice thickness, 2 mm; pixel size <0.3 × 0.3 mm(2)). Images were read by five neuroradiologists blinded to histopathologic findings. ROC curves were constructed with AUC assessment using a bootstrap method. Histopathology identified 41 eyes without ON invasion and 25 with prelaminar, 18 with intralaminar and 12 with postlaminar invasion. All but one were postoperatively classified as stage I by the International Retinoblastoma Staging System. The accuracy of CE-T1 sequences in identifying ON invasion was limited (AUC = 0.64; 95 % CI, 0.55 - 0.72) and not confirmed for postlaminar invasion diagnosis (AUC = 0.64; 95 % CI, 0.47 - 0.82); high specificities (range, 0.64 - 1) and negative predictive values (range, 0.81 - 0.97) were confirmed. HR-MRI with surface coils is recommended to appropriately select retinoblastoma patients eligible for primary enucleation without the risk of IRSS stage II but cannot substitute for pathology in differentiating the first degrees of ON invasion. • HR-MRI excludes advanced optic nerve invasion with high negative predictive value. • HR-MRI accurately selects patients eligible for primary enucleation. • Diagnosis of early stages of optic nerve invasion still relies on pathology. • Several physiological MR patterns may mimic optic nerve invasion.

Comparison of Staging Systems for Extraocular Retinoblastoma

Different staging systems for extraocular retinoblastoma have been published, but to date they have not been validated in large cohorts. To review 533 patients (and pathology slides) with retinoblastoma included in 4 protocols (January 1, 1988, to December 31, 2009) who received uniform treatment. Retrospective review in a hospital setting. A critical analysis for detecting inconsistencies and omissions was performed. Patients were reclassified according to the modified St Jude Children's Research Hospital staging system, Grabowski-Abramson staging system, International Retinoblastoma Staging System (IRSS), and American Joint Committee on Cancer TNM staging system. The main outcome measure was disease-free survival (DFS), considering only extraocular relapse as an event. In the IRSS and the St Jude system, higher stages correlated with poorer DFS. For intraocular disease, only the TNM system and the IRSS included pathological definitions, and all systems except for the IRSS included substages without differences in DFS. Omissions of factors significantly associated with lower DFS included scleral invasion by the TNM system and massive choroidal invasion by the Grabowski-Abramson system. The St Jude system omits postlaminar optic nerve involvement, but this omission did not correlate significantly with lower DFS because these patients received intensive therapy. No differences in DFS were observed among substages for metastatic disease except for the presence of central nervous system involvement. All staging systems had inconsistencies in definitions of extent of disease. No system provides guidelines for imaging. Only the IRSS and the St Jude system allowed for grouping of patients with increasing risk of extraocular relapse. For lower stages, only the IRSS considers all unequivocal pathological prognostic factors. For higher stages, all systems had redundant information, resulting in an excess of substages.

Extraocular retinoblastoma in Indian children: clinical, imaging and histopathological features.

TO STUDY EYES WITH EXTRAOCULAR DISSEMINATION (EORB), WITH THE FOLLOWING AIMS: first to establish the mean lag period and to understand various reasons for delayed presentation, second to study their imaging profiles and third to analyze histopathological features of eyes enucleated after neoadjuvant chemotherapy. Prospective study of clinical and imaging features of EORBs (stage III and IV International Retinoblastoma Staging System) presenting to a tertiary eye care centre. Histopathological features of eyes enucleated after receiving neoadjuvant chemotherapy were analyzed. A pictorial illustration of the varied imaging profile of EORB was also presented. Over a period of one year, 97 eyes were diagnosed with retinoblastoma; 32 children (36 eyes) (37.1%) had EORB. Mean age 3.6±1.9 years, 71.9% males, 71.9% unilateral, 3.1% with positive family history and 40.6% with metastasis. On imaging, there was extrascleral involvement in 22.2%, involvement of orbital part of optic nerve in 33.3%, involvement of central nervous system in 27.8% and orbital wall involvement in 2.9% eyes. On histopathological analysis of eyes enucleated after neoadjuvant chemotherapy, 25.0% had no residual viable tumour tissue and rest all tumours were poorly differentiated. There are very few human malignancies where definitive treatment is started without any confirmed histopathological diagnosis and imaging plays an important role in diagnosis and appropriate staging of the disease. Chemotherapy has a variable effect on EORB, 75.0% of eyes with EORB had residual viable tumour tissue when enucleated after receiving neoadjuvant chemotherapy.

MRI findings at baseline and after neoadjuvant chemotherapy in orbital retinoblastoma (IRSS stage III)

BackgroundPublished findings on MRI results in retinoblastoma patients treated with neoadjuvant chemotherapy (NACT) are lacking. The present study evaluates the role of MRI in International Retinoblastoma Staging System (IRSS) stage...

Histopathology of retinoblastoma: Does standardization make a difference in reporting?

The International Retinoblastoma Staging Working Group (IRSWG) provided guidelines for tissue handling of eyes enucleated for retinoblastoma. We adopted these guidelines from January 2009. Reviewing histopathology slides between January 2006 and December 2010 we found significantly more number of eyes with massive choroidal, optic nerve, and anterior segment invasion by tumor cells in the post-IRSWG era. The guidelines provided by the IRSWG; in addition to being standardized; recognize more eyes with histopathologic risk factors compared to techniques applied in the past. This may translate to more children receiving adjuvant chemotherapy and contribute to reduced mortality rates in the future.

Outcome, Pathologic Findings, and Compliance in Orbital Retinoblastoma (International Retinoblastoma Staging System Stage III) Treated with Neoadjuvant Chemotherapy: A Prospective Study

The present study prospectively evaluated outcome, pathologic findings, and compliance in orbital retinoblastoma patients (International Retinoblastoma Staging System [IRSS] stage III). Prospective study and case series. Twenty-eight consecutive IRSS stage III retinoblastoma patients were enrolled prospectively in the study after ethics committee approval and written informed consent. Planned therapy for patients included treatment with a uniform protocol consisting of neoadjuvant chemotherapy followed by enucleation, adjuvant radiotherapy, and chemotherapy. Prospective computerized data entry and telephone contact were undertaken to improve compliance, a major issue in treatment of orbital retinoblastoma. Event-free survival (EFS) and overall survival (OS) were calculated using Kaplan-Meier survival analysis. The difference between groups was analyzed using the log-rank test. Median follow-up was 14.75 months (range, 2.23-26.3 months). The OS for all patients was 40.4% and the EFS was 33.33% at a follow-up of 26.3 months. The median EFS and OS were 10.37 months and 15.73 months, respectively. At baseline, bilateral retinoblastoma predicted inferior EFS (P = 0.0006) and OS (P = 0.0081). Twenty-two of 28 patients underwent enucleation, and viable tumor was present in 21 of 22 enucleated specimens (95%). Neoadjuvant chemotherapy prevented orbital exenterations. Presence of tumor in the cut end of the optic nerve significantly correlated with inferior EFS (P = 0.012) and OS (P = 0.0098). Central nervous system metastasis was the most common site of relapse and death. The overall rate of compliance with treatment was 67.8% (19/28), which was twice the compliance rate at the authors' center before initiation of the present study. There is a paucity of information in the literature on outcomes and pathologic findings after neoadjuvant chemotherapy in IRSS stage III retinoblastoma treated with a uniform treatment protocol, and as far as the authors are aware, there has been no prospective study. Neoadjuvant chemotherapy was able to avoid exenteration in all operated patients; however, residual viable tumor was present in 95% of enucleated specimens. Bilaterality and tumor in the optic nerve cut end after neoadjuvant chemotherapy were associated with inferior outcome. Compliance could be improved with computerized data entry and regular telephone contact.

Role of PET/CT in Staging and Evaluation of Treatment Response After 3 Cycles of Chemotherapy in Locally Advanced Retinoblastoma: A Prospective Study

The present study prospectively evaluated the role of (18)F-FDG PET/CT for staging, neoadjuvant chemotherapy response evaluation, and final outcome assessment in International Retinoblastoma Staging System (IRSS) stage III retinoblastoma. Twenty-five consecutive IRSS stage III patients, with a median age of 3 y, were prospectively enrolled after ethics approval. All patients received neoadjuvant chemotherapy followed by enucleation, radiotherapy, and adjuvant chemotherapy. PET/CT was performed at baseline (PET/CT-1) and after 3 cycles of neoadjuvant chemotherapy (PET/CT-2). All 25 patients underwent PET/CT-1, and 21 of 25 patients underwent PET/CT-2. PET/CT-1 was compared with routine staging, and response on PET/CT-2 was assessed by criteria from the European Organization for Research and Treatment of Cancer response. Event-free survival (EFS) and overall survival (OS) were calculated using Kaplan-Meier survival analysis, and differences between the groups were compared using log-rank test. A P value of 0.05 or less was considered significant. Increased (18)F-FDG uptake was noted in primary extraocular tumor in all patients, except 5 with bilateral retinoblastoma (one eye with advanced and the other eye with intraocular disease) in whom the intraocular tumor did not show (18)F-FDG uptake. Five of 22 IRSS stage IIIA patients with clinically negative cervical lymph node involvement were found to have uptake in cervical lymph nodes on PET/CT-1, and 2 of 3 IRSS stage IIIB patients with pathologically confirmed cervical lymph node involvement did not show any uptake in the involved lymph nodes. No significant difference in EFS and OS was seen between IRSS stage IIIA and IIIB patients using routine staging or PET/CT staging (P ≥ 0.05); however, there was a trend toward better OS in patients with IRSS stage IIIB disease on PET/CT (P = 0.065). There was no significant discordance between routine staging and PET/CT staging (P = 0.256). The 8 patients with optic nerve uptake had lower EFS (P = 0.0001) and OS (P = 0.0009) than did 17 patients without optic nerve uptake on PET/CT-1. The 17 patients with complete response or partial response had better EFS (P = 0.042) and OS (P = 0.026) than did the 4 patients with progressive disease on PET/CT-2. Optic nerve uptake at baseline on PET/CT and response after neoadjuvant chemotherapy according to criteria from the European Organization for Research and Treatment of Cancer are strong predictors of EFS and OS in IRSS stage III retinoblastoma.

Bone Marrow Aspirations and Lumbar Punctures in Retinoblastoma at Diagnosis

Few studies have suggested that routine bone marrow (BM) and cerebrospinal fluid (CSF) evaluation is not needed in all patients with retinoblastoma. Although the International Retinoblastoma Staging System was developed recently, there remain no clear stage-specific guidelines with regard to the need for BM and CSF evaluations as part of the metastatic workup for patients with retinoblastoma. This is a retrospective study analyzing results of CSF cytology and BM evaluation at presentation/diagnosis in patients with retinoblastoma registered at our center from June, 2003 to June, 2009. Only cases with both BM biopsy and lumbar puncture were included. Of the 259 evaluable patients, 18 (7%) were positive for metastasis either in CSF and/or BM. Although 7 of these had overt metastasis at presentation (stage IV), 1 belonged to stage II and 10 to stage IIIa. No stage 0 or I patient tested positive despite presence of histopathologic high-risk factors. This is the largest study evaluating the role of metastatic workup in patients with retinoblastoma at presentation. We conclude that CSF and BM evaluation is not required in patients with stage 0 and I retinoblastoma at presentation. No definitive recommendation could be made for stage II patients; while stage III and IV patients must certainly be evaluated.

Treatment and Outcome of Nonmetastatic Extraocular Retinoblastoma With a Uniform Chemotherapy Protocol

Nonmetastatic extraocular retinoblastoma is a common entity in South-East Asia. We did a retrospective study of patients treated for isolated extraocular retinoblastoma, that is, International retinoblastoma staging system stages II and III, using a uniform chemotherapy protocol at our oncology center, between June 2003 and June 2008. Out of the 25 patients having nonmetastatic extraocular retinoblastoma, 6 were in stage II, and 19 in stage III. The probability of event-free survival was 0.54 at 18 months of follow-up with no significant difference between the 2 stages and the presence of optic nerve involvement; 11 out of 13 relapses were systemic. This is the largest case series of nonmetastatic extraocular retinoblastoma from South-East Asia.

Proceedings of the Consensus Meetings From the International Retinoblastoma Staging Working Group on the Pathology Guidelines for the Examination of Enucleated Eyes and Evaluation of Prognostic Risk Factors in Retinoblastoma

Retinoblastoma is the most common intraocular malignant childhood tumor in need of prospective clinical trials to address important unanswered questions about biology, treatment, and prognostic factors. Currently, there is controversy about the definitions for choroidal invasion and an inconsistency in the handling of eyes with retinoblastoma. The International Retinoblastoma Staging Working Group (IRSWG) composed of 58 participants from 24 countries on 4 continents had a series of Internet meetings to discuss the staging and tissue handling guidelines to reach consensus for adequate processing, establishing definitions of histopathologic risk factors, and reporting of enucleated eyes with retinoblastoma to serve as the basis for clinical trials and studies to validate the proposed criteria. The meetings were facilitated by the International Outreach Program of the St. Jude Children's Research Hospital through Cure4Kids. The retinoblastoma guidelines from the Children's Oncology Group, the French Society for Pediatric Cancers, the Association of Directors of Anatomic and Surgical Pathology, and some published data were the basis for this consensus document. Discussions of the feasibility, practicality, and efficacy of the guidelines and criteria resulted in this report. The consensus definitions reached included definition of massive choroidal invasion stated as a maximum diameter of invasive tumor focus of 3 mm or more that may reach the scleral tissue. Focal choroidal invasion is defined as a tumor focus of less than 3 mm and not reaching the sclera. Optic nerve invasion is classified as prelaminar, laminar, retrolaminar, or tumor at surgical margin, and the measurement of the depth of invasion should also be recorded. These guidelines also address handling of the enucleated eye with retinoblastoma in an efficient, practical, and feasible manner for a meaningful diagnosis. The consensus criteria reached by the IRSWG should be validated through prospective clinical trials and studies.

Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma.

Retinoblastoma is the most common intraocular malignant childhood tumor in need of prospective clinical trials to address important unanswered questions about biology, treatment, and prognostic factors. Currently, there is controversy about the definitions for choroidal invasion and an inconsistency in the handling of eyes with retinoblastoma. The International Retinoblastoma Staging Working Group (IRSWG) composed of 58 participants from 24 countries on 4 continents had a series of Internet meetings to discuss the staging and tissue handling guidelines to reach consensus for adequate processing, establishing definitions of histopathologic risk factors, and reporting of enucleated eyes with retinoblastoma to serve as the basis for clinical trials and studies to validate the proposed criteria. The meetings were facilitated by the International Outreach Program of the St. Jude Children's Research Hospital through Cure4Kids. The retinoblastoma guidelines from the Children's Oncology Group, the French Society for Pediatric Cancers, the Association of Directors of Anatomic and Surgical Pathology, and some published data were the basis for this consensus document. Discussions of the feasibility, practicality, and efficacy of the guidelines and criteria resulted in this report. The consensus definitions reached included definition of massive choroidal invasion stated as a maximum diameter of invasive tumor focus of 3 mm or more that may reach the scleral tissue. Focal choroidal invasion is defined as a tumor focus of less than 3 mm and not reaching the sclera. Optic nerve invasion is classified as prelaminar, laminar, retrolaminar, or tumor at surgical margin, and the measurement of the depth of invasion should also be recorded. These guidelines also address handling of the enucleated eye with retinoblastoma in an efficient, practical, and feasible manner for a meaningful diagnosis. The consensus criteria reached by the IRSWG should be validated through prospective clinical trials and studies.

World disparities in risk definition and management of retinoblastoma: A report from the International Retinoblastoma Staging Working Group

Following from the publication of the International Retinoblastoma Staging System, an open internet discussion group was created at the www.cure4kids.org resource. The results of a survey distributed among participants are discussed. Although most patients with retinoblastoma were treated under prospective protocols, there was a wide variation in the definition of risk criteria and in the criteria for giving adjuvant chemotherapy following enucleation. Definition of high-risk histological features and the criteria for use of adjuvant therapy will be standardized in future studies. Internet meetings are a valuable mechanism for enabling participation from under-resourced countries in the development of cooperative studies.

International retinoblastoma staging system helps to bridge the gap

International retinoblastoma staging system helps to bridge the gap

A proposal for an international retinoblastoma staging system

Although intra-retinal tumor has long been staged presurgically according to the Reese-Ellsworth (R-E) system, retinoblastoma differs from other pediatric neoplasms in never having had a widely accepted classification system that encompasses the entire spectrum of the disease. Comparisons among studies that consider disease extension, risk factors for extra-ocular relapse, and response to therapy require a universally accepted staging system for extra-ocular disease. A committee of retinoblastoma experts from large centers worldwide has developed a consensus classification that can encompass all retinoblastoma cases and is presented herein. Patients are classified according to extent of disease and the presence of overt extra-ocular extension. In addition, a proposal for substaging considering histopathological features of enucleated specimens is presented to further discriminate between Stage I and II patients. The following is a summary of the classification system developed-Stage 0: Patients treated conservatively (subject to presurgical ophthalmologic classifications); Stage I: Eye enucleated, completely resected histologically; Stage II: Eye enucleated, microscopic residual tumor; Stage III: Regional extension [(a) overt orbital disease, (b) preauricular or cervical lymph node extension]; Stage IV: Metastatic disease [(a) hematogenous metastasis: (1) single lesion, (2) multiple lesions; (b) CNS extension: (1) prechiasmatic lesion, (2) CNS mass, (3) leptomeningeal disease]. A proposal is also presented for substaging of enucleated Stages I and II eyes. The proposed staging system is the product of an international effort to adopt a uniform staging system for patients with retinoblastoma to cover the whole spectrum of the disease.