Retinoblastoma Staging Research Articles

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.

A visual approach to providing prognostic information to parents of children with retinoblastoma

Parents must rapidly assimilate complex information when a child is diagnosed with cancer. Education correlates with the ability to process and use medical information. Graphic tools aid reasoning and communicate complex ideas with precision and efficiency. We developed a graphic tool, DePICT (Disease-specific electronic Patient Illustrated Clinical Timeline), to visually display entire retinoblastoma treatment courses from real-time clinical data. We report retrospective evaluation of the effectiveness of DePICT to communicate risk and complexity of treatment to parents. We assembled DePICT graphics from multiple children on cards representing each stage of intraocular retinoblastoma. Forty-four parents completed a 14-item questionnaire to evaluate the understanding of retinoblastoma treatment and outcomes acquired from DePICT. As a proposed tool for informed consent, DePICT effectively communicated knowledge of complex medical treatment and risks, regardless of the education level. We identified multiple potential factors affecting parent comprehension of treatment complexity and risk. These include language proficiency (p=0.005) and age-related experience, as younger parents had higher education (p=0.021) but lower comprehension scores (p=0.011), regardless of first language. Provision of information at diagnosis concerning long-term treatment complexity helps parents of children with cancer. DePICT effectively transfers knowledge of treatments, risks, and prognosis in a manner that offsets parental educational disadvantages.

International retinoblastoma staging system helps to bridge the gap

International retinoblastoma staging system helps to bridge the gap

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.

Genomic differences between retinoma and retinoblastoma

Introduction. Genomic copy number changes are involved in the multi-step process transforming normal retina in retinoblastoma after RB1 mutational events. Previous studies on retinoblastoma samples led to a multi-step model in which after two successive RB1 mutations, further genomic changes accompany malignancy: 1q32.1 gain is followed by 6p22 gain, that in turn is followed by 16q22 loss and 2p24.1 gain. Retinoma is a benign variant of retinoblastoma that was initially considered a tumor regression, but recent evidences suggest that it rather represents a pre-malignant lesion. Genetic studies on retinoma tissue have rarely been performed. Materials and methods. We investigated by Real-Time qPCR, copy number changes of candidate genes located within the 4 hot-spot regions (MDM4 at 1q32.1, MYCN at 2p24.1, E2F3 at 6p22 and CDH11 at 16q22) in retina, retinoma and retinoblastoma tissues from two different patients. Results. Our results demonstrated that some copy number changes thought to belong to early (MDM4 gain) or late stage (MYCN and E2F3 gain) of retinoblastoma are already present in retinoma at the same (for MDM4) or at lower (for MYCN and E2F3) copy number variation respect to retinoblastoma. CDH11 copy number is not altered in the two retinoma samples, but gain is present in one of the two retinoblastomas. Discussion. Our results suggest that MDM4 gain may be involved in the early transition from normal retina to retinoma, while MYCN and E2F3 progressive gain may represent driving factors of tumor progression. These results also confirm the pre-malignant nature of retinoma.

Genetics and management of retinoblastoma

Retinoblastoma is the most common intraocular tumor in childhood. In majority of early stage retinoblastoma, the eyeballs as well as vision can be preserved with chemotherapy and local intraocular therapy with laser or photocoagulation. However, more than half the patients in India and other developing nations present in advanced stage of the disease. This article reviews the genetics, clinical approach, and treatment options for retinoblastoma focussing on advances in chemotherapy for intraocular retinoblastoma (chemoreduction), as well as improvement in survival in advanced retinoblastoma with surgery, chemotherapy, radiotherapy, and bone marrow transplantation.

Retinoblastoma—MR appearance using a surface coil in comparison with histopathological results

The purpose of this work was to evaluate the characteristic appearance of untreated retinoblastoma on a large sample in comparison to the histological findings after therapeutical enucleation. In a prospective clinical trial 46 children with retinoblastoma in 63 affected untreated eyes were examined under general anesthesia on MRI using a 1.5-T system. The examinations were performed with a special surface coil applying an examination protocol including fast T2- and T1-weighted spin echo sequences and additional fast T1-WI after intravenous injection of Gd-DTPA in different planes. The imaging results were compared to the histopathological findings in 29 patients with 30 affected eyes. Comparing MRI findings and histopathological results, optic nerve infiltration was detected with a sensitivity of 53.8% and a specificity of 82.3% on MRI, infiltration of the choroid with a sensitivity of 75.0% and a specificity of 100.0%, and the degree of tumor calcification with a sensitivity of 91.7% and a specificity of 88.9%. In this study the characteristic MR appearance of untreated retinoblastoma was evaluated. MRI was helpful in relevant aspects of pretherapeutical retinoblastoma staging, deficits remain regarding optic nerve infiltration.

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.

CONTINUING CHALLENGES IN THE MANAGEMENT OF RETINOBLASTOMA WITH CHEMOTHERAPY

The management of retinoblastoma has gradually changed over the past 10 years. Over 95% of children with retinoblastoma in the United States are cured with modern techniques. The challenge remains, however, in maintaining the eye and vision. There is a trend away from enucleation and external beam radiotherapy toward focal conservative treatments involving primary chemoreduction in conjunction with thermotherapy and cryotherapy. This is related to earlier detection of the disease, recognition of more effective chemotherapeutic agents, more focused local treatment modalities, and, most importantly, knowledge of the long-term risks of external beam radiotherapy. Enucleation is still preferable for retinoblastoma that fills most of the eye, especially when the disease is unilateral or when there is concern for tumor invasion into the optic nerve, choroid, or orbit. The orbital integrated implant is placed after enucleation and provides acceptable prosthesis motility and appearance. External beam radiotherapy is still vital for treating advanced retinoblastoma, especially when there is diffuse vitreous or subretinal seeding after failure of other methods and preservation of vision is a priority. The most important recent advance in the management of retinoblastoma is the use of intravenous chemotherapy for tumor reduction, a technique of neoadjuvant chemotherapy termed "chemoreduction." This is followed by tumor consolidation with focal measures such as thermotherapy, cryotherapy, and plaque radiotherapy. This strategy provides reduced tumor volume and often permits consolidation with methods other than radiotherapy. It appears that vision can be preserved in some cases with these methods, avoiding some of the local complications like radiation cataract or macular edema that have been found with radiotherapy techniques. External beam radiotherapy and enucleation can now be avoided in most cases of Reese-Ellsworth groups I (minimal disease) through IV (moderate disease) retinoblastoma. The most advanced stage of retinoblastoma, Reese-Ellsworth group V, continues to provide the greatest difficulty for management, and external beam radiotherapy and enucleation are often employed in addition to chemoreduction to save the child's life. A collaborative prospective study in North America is currently under way to further study the benefits and risks of chemoreduction for minimal, moderate, and advanced retinoblastoma.

Rubeosis lridis in Retinoblastoma: Histologic Findings and the Possible Role of Vascular Endothelial Growth Factor in Its Induction

Iris neovascularization (rubeosis iridis) is a common finding in eyes harboring retinoblastoma. The purpose of the current study is to evaluate the histologic factors that may affect the development of rubeosis iridis in eyes with retinoblastoma and to examine whether vascular endothelial growth factor (VEGF), a hypoxia-induced angiogenic factor, is produced by hypoxic retinoblastoma and retinal cells in these eyes. One hundred eighty-one enucleated eyes containing retinoblastoma were the source for the current study. Histologic slides were evaluated for the presence and degree of rubeosis iridis as well as for other histologic factors. Univariate and multivariate statistical analyses were performed to find a correlation between rubeosis iridis and the other histologic factors. Eight of the eyes underwent in situ hybridization with a specific VEGF mRNA probe to locate tumor and retinal cells that may produce this hypoxia-induced angiogenic factor. The amount of tumor necrosis as well as choroidal and optic nerve invasion was found to be one of the most important factors that correlated with the presence and degree of rubeosis iridis in the examined eyes. All eight eyes that underwent in situ hybridization analysis showed strong signals of VEGF mRNA in retinoblastoma cells around necrotic regions and in the outer nuclear layers in areas of detached retina. There exists an association between rubeosis iridis and histologic factors found in advanced stages of retinoblastoma, especially the amount of tumor necrosis. Vascular endothelial growth factor may well be an angiogenic factor that is secreted by the hypoxic retinoblastoma and retinal cells and, reaching the iris, causes (presumably in collaboration with other factors) rubeosis iridis.

Retinoblastoma: CT and MRI

To evaluate the effectiveness of CT and MRI at 0.5 T in the diagnosis and staging of retinoblastoma, we studied 11 patients in whom retinoblastoma was clinically suspected. Nine of the eleven had surgically proven retinoblastoma; in the other two a diagnosis of Coats' disease was made. MRI was not as specific as CT for diagnosing retinoblastoma, due to its lack of sensitivity in detecting calcification; it did, however, have superior contrast resolution. On MRI, Coats' disease was reliably diagnosed and easily differentiated from retinoblastoma. Moreover, the greater ability of MRI to differentiate subretinal fluid from tumour also confers high accuracy in measuring tumour size. CT is still the study of choice in the diagnosis of retinoblastoma, but when MRI is available, it should be performed for better differentiation from lesions such as Coats' disease.

Chemotherapy for retinoblastoma: Where do we go from here?: A review of published literature and meeting abstracts, including discussions during the Vth International Symposium on Retinoblastoma, October 1990

The history of the application of chemotherapy in the management of retinoblastoma (RB) may conveniently be divided into three eras: initial enthusiasm (from early 1950s to mid 1970s), realism (from late 1970s to mid 1980s) and possibility (from mid 1980s to the future). Available data from each of these eras are reviewed in the clinical categories of: intraocular RB, micrometastatic RB and overt dissemination. The latter is further sub-classified into: orbital invasion, central nervous system involvement and systemic metastases. Experimental models are described with particular emphasis on future directions. Early reports led to initial optimism subsequently dampened by a more critical approach. Recent results with increasingly effective chemotherapeutic regimens offer the possibility of a valid contribution in each of the above clinical settings. A multi-modality approach is recommended optimizing a combination of the most active drugs with continuing refinements of other techniques. In selected patients with intraocular, and particularly bilateral RB, visual outcome may be enhanced by the combined use of non-surgical modalities. Adjuvant treatment of presumed micrometastases needs to be studied within risk categories defined by prognostic factors. Invasion of the ocular coats and/or of the optic nerve are the most relevant factors but there are continued difficulties in defining the extent of involvement and eligibility criteria for such a strategy. Overt dissemination has recently been demonstrated to be curable in each of the three subgroups above. Intensive regimens incorporating cyclophosphamide, vincristine, cisplatinum, etoposide and possibly doxorubicin, plus intrathecal agents in combination with radiation therapy and, in some instances supplemented by bone marrow transplantation have produced promising results. Multi-institutional collaboration has been encouraged by the recently formed International Committee for the Staging and Management of Retinoblastoma, opening the way for prospective clinical trials. At the same time both laboratory and clinical experimental studies are being pursued and may produce further improvements in currently available strategies.

Treatment of bilateral retinoblastoma stage V at the Curie Foundation. 33 cases.

A retrospective study was undertaken on 33 patients with bilateral retinoblastoma in whom one eye at least was classified as stage IV or V (Reese-Ellsworth classification). In most cases the other eye had been enucleated elsewhere. Conservative therapy consisted of primary chemotherapy (vincristine, actinomycin, cyclophosphamide) followed by external beam irradiation, six courses of chemotherapy and, if necessary, by cobalt-60 plaques, xenon arc photocoagulation or secondary enucleation. Ten patients were lost to follow-up, eight patients died or are currently being treated for recurrence, 15 patients are alive and free from disease and 42% of eyes at stage IV or V were saved. These results indicate that primary chemotherapy does not improve the final outcome of stage IV or V retinoblastoma, as compared with primary irradiation.

Correlation of CD24 expression with histological grading and TNM staging of retinoblastoma.

Objective:Correlation of CD24 expression with histological grading and TNM staging of retinoblastoma.Methods:This cross-sectional study was conducted in the Department of Pathology, BMSI, JPMC and NICH from 1st January 2009 to 31st December 2013. A total 68 diagnosed cases of retinoblastoma were selected for CD24 immuno staining. The data was analyzed by using SPSS version 22.Results:Out of 68 cases 7.35% showed grade 1 followed by 11.76% in G2, 26.47% in G3 and 54.41% in G4. Majority of cases i.e. 60.29% in stage IV followed by 19.11% in stage I, 10.29% each in stage II and stage III. CD24 immuno staining positivity was seen in majority of grade 3 and grade 4. In grade 3, 38.88% showed moderate and 22.22% strong immuno reaction. Amongst grade 4, 40.54% showed moderate and 13.51% strong positive. Variable immuno pattern was observed according to TNM staging. In stage I, 46.15% showed moderate and 7.69% strong positivity, while in stage II, 57.14% were negative for saining. In stage III, 42.85% were negative while 28.57% each showed moderate and strong staining. Majority of cases in stage IV i.e. 48.78% were negative for staining while 34.14%, 17.07% showed moderate and severe CD24 immuno staining.Conclusion:Majority of grade I retinoblastoma were in TNM stage I & II and mostly were immuno negative. Lymph node and distant metastatic cases were 75% in G4 and 25% in G3, all of them showed moderate to strong immunoreactivity. These results showed that CD24 expression may be a marker of poor prognosis in retinoblastoma. Whereas TNM staging of retinoblastomas with CD24 expression had varying pattern and showed no significant correlation between them.

TREATMENT OF RETINOBLASTOMA (RETINAL GLIOMA) SURGICALLY AND BY IRRADIATION

In 1936, we published a preliminary report 1 on the treatment of bilateral retinoblastoma by a technic of fractionated irradiation which had not previously been used for this form of cancer. That report was based on 6 cases of bilateral growths in which one eye had been removed and the other irradiated in an attempt to control the growth and conserve vision. One of the purposes of this communication is to give the follow-up to date in these 6 cases and to submit preliminary data on 4 more recent cases of bilateral retinoblastoma in which the treatment was similar. In the present report we shall also discuss the other clinical forms and stages of retinoblastoma (unilateral tumors, advanced bilateral growths with the vision irreparably destroyed by the time of admission, postoperative recurrent retinoblastoma and widely disseminated retinoblastoma), in the treatment of which radiation therapy as a means of conserving vision

RETINOBLASTOMA

The earlier stages of retinoblastoma, when the process is situated in the vitreous, are well known and easily recognized. When the fundus has become obscured, however, diagnosis may be difficult, as is illustrated in the following case. REPORT OF A CASE A boy, aged 4 years, fell against a chair, striking his left eye on a rung. The eye was red for a while and then began to shrink. When first seen, eight months later, the globe was small, red and somewhat firm. The outstanding feature was the appearance of the cornea. This was perfectly opaque, and presented the grayish-brown coloration characteristic of blood-staining. Except for a small staphyloma below, no further details could be made out. In this case, the history, the blood-stained cornea and the shrinkage of the globe seemed to indicate the presence of traumatic iridocyclitis. On enucleation, however, the eye was found to contain a retinoblastoma.