Tandem high-dose chemotherapy followed by autologous stem cell transplantation: An infant with trilateral retinoblastoma.

BACKGROUND: Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Advanced RB, associated with exceedingly poor prognosis, requires more intensive multiagent chemotherapy than conventional regimens. Rescue of the bone marrow after intensive chemotherapy is achieved with stem cell transplantation. The sequential courses (tandem transplantation) of high-dose chemotherapy followed by autologous stem cell transplantation allow for even greater dose intensity in consolidation with the potential to use different active chemotherapeutics at each transplant and have proven feasible and successful in treating children with recurrent/refractory solid tumors. CASE DESCRIPTION: We report an infant with trilateral high-risk RB who received tandem high-dose chemotherapy (HDC) followed by autologous stem cell transplantation after the conventional chemotherapy. A 5-month-old female patient presented with strabismus, and the ophthalmoscopic examination showed intraocular tumoral lesions in both eyes. Magnetic resonance imaging (MRI) concluded the trilateral retinoblastoma diagnosis due to a tumoral mass in the optic chiasm. The follow-up ophthalmologic examinations and the MRI detected stable disease after six cycles of multiagent chemotherapy. CONCLUSIONS: Rescue with autologous stem cell transplantation after HDC allows for an increase in chemotherapy intensity. Tandem transplantation provides the chance to perform different chemotherapeutics at each transplant and enables an increase in the chemotherapy intensity, thus providing a positive effect on disease-free survival.

Histopathology and molecular pathology of pediatric pineal parenchymal tumors.

Pineal parenchymal tumors in children are rare. They consist of two main types, pineoblastoma (PB) and pineal parenchymal tumor of intermediate differentiation (PPTID), which are World Health Organization (WHO) grade 4 and grade 2-3 respectively. PBs are divided into four distinct molecular groups: PB-miRNA1, PB-miRNA2, PB-RB1, and PB-MYC/FOXR2. PB-RB1 and PB-MYC/FOXR2 affect young children and are associated with a dismal prognosis. PB-miRNA1 and PB-miRNA2 groups affect older children and follow a more favorable course. They are characterized by mutually exclusive alterations in genes involved in miRNA biogenesis, including DICER1, DROSHA, and DGCR8. They may be sporadic or may represent one manifestation of DICER1 syndrome. PB-RB1 tumors show alterations in the RB1 gene and may develop in the setting of congenital retinoblastoma, a condition known as "trilateral retinoblastoma." In the pediatric population, PPTIDs typically affect adolescents. They are characterized by small in-frame insertions in the KBTBD4 gene which is involved in ubiquitination.

Asynchronous pineoblastoma is more likely after early diagnosis of retinoblastoma: a meta-analysis.

PURPOSE: To determine the risk of patients with an early diagnosis of heritable retinoblastoma being diagnosed with TRb (or pineoblastoma) asynchronously in a later stage and its effect on screening. METHODS: We updated the search (PubMed and Embase) for published literature as performed by our research group in 2014 and 2019. Trilateral retinoblastoma (TRb) patients were eligible for inclusion if identifiable as unique and the age at which TRb was diagnosed was available. The search yielded 97 new studies. Three new studies and eight new patients were included. Combined with 189 patients from the previous meta-analysis, the database included 197 patients. The main outcome was the percentage of asynchronous TRb in patients diagnosed before and after preset age thresholds of 6 and 12 months of age at retinoblastoma diagnosis. RESULTS: Seventy-nine per cent of patients with pineoblastoma are diagnosed with retinoblastoma before the age of 12 months. However, baseline MRI screening at time of retinoblastoma diagnosis fails to detect the later diagnosed pineal TRb in 89% of patients. We modelled that an additional MRI performed at the age of 29 months picks up 53% of pineoblastomas in an asymptomatic phase. The detection rate increased to 72%, 87% and 92%, respectively, with 2, 3 and 4 additional MRIs. CONCLUSIONS: An MRI of the brain in heritable retinoblastoma before the age of 12 months misses most pineoblastomas, while retinoblastomas are diagnosed most often before the age of 12 months. Optimally timed additional MRI scans of the brain can increase the asymptomatic detection rate of pineoblastoma.

Clinical and magnetic resonance imaging features of 14 patients with trilateral retinoblastoma.

BACKGROUND: Our study aimed to comprehensively investigate the age of onset, magnetic resonance imaging (MRI) features, and prognosis of children with trilateral retinoblastoma (TRB). METHODS: We included 14 patients with TRB diagnosed or followed up in our hospital. The age of onset and MRI features of the intraocular tumor and intracranial lesions were evaluated. A follow-up study was also conducted. RESULTS: A total of 11 participants were diagnosed with concurrent TRB at the age of 11.1±7.4 months, and 3 participants had late-onset TRB at age 37±19.1 months. The incidence of TRB with unilateral eye involvement was 7.1% (1/14). The intraocular tumors showed intense enhancement in contrast-enhanced T1-weighted images (WI) and significant diffusion restriction in diffusion WI (DWI) with an apparent diffusion coefficient (ADC) of (0.619±0.22)×10-3 mm2/s. The intracranial lesions showed similar DWI aspects with an ADC value of (0.680±0.206)×10-3 mm2/s. Therapeutically, 8 participants had a period of intraocular tumor stabilization and significant intracranial lesion volume reduction after chemotherapy, and 6 participants had given up treatment. Only 2 participants who simultaneously received high-dose chemotherapy and autologous hematopoietic stem cell rescue were still alive with no recurrence at 24 and 54 months of follow-up. The 1-, 2-, and 3-year overall survival (OS) rates were 80%, 18.75%, and 12.5%, respectively. CONCLUSIONS: Patients with unilateral or bilateral RB can develop TRB. The intraocular and intracranial tumors showed slightly different ADC values. High-dose chemotherapy, combined with stem cell rescue can significantly improve survival. A long term and scheduled follow-up before 60 months of age is necessary for screening later-onset TRB patients.

Trilateral retinoblastoma: A systematic review of 211 cases.

We conducted a systematic review of 72 studies to characterize trilateral retinoblastomas. Kaplan-Meier analysis was used to estimate survival, and statistical significance was assessed by using a log-rank test. We analyzed 211 cases of trilateral retinoblastomas. The average age of onset of retinoblastoma was 0.79 ± 1.38 years, and the average latency period between the onset of retinoblastomas and trilateral retinoblastomas was 1.49 ± 1.76 years. The brain tumors were found before the retinoblastoma diagnosis in 6 cases (3.1%), concurrently in 61 cases (32.1%), and after the retinoblastoma diagnosis in 123 cases (64.7%). Pineal tumors were found in 155 cases (73.4%) and sellar tumors in 46 cases (21.8%). The overall median survival was 10.3 months (95% CI, 8.5-13) and the 5-year survival rate was 15.7%. Central nervous system symptoms were variable and associated with shorter survival in univariate and multivariate analyses. The survival time in patients who received high-dose chemotherapy with stem cell transplant was significantly longer (p = 0.0067) than that of with or without conventional chemotherapy. Twelve long-term survivors were reported, and of these, six patients were treated with high-dose chemotherapy with stem cell transplant and six patients were treated with conventional chemotherapy. It is important that survivors continue to undergo regular medical surveillance in order to detect trilateral retinoblastoma at a potentially curative stage. Trilateral retinoblastoma patients with an irradiation history had shorter survival than those without irradiation history for retinoblastoma. High-dose chemotherapy should be considered as a potential treatment option for trilateral retinoblastomas.

Quiste benigno de la glándula pineal en paciente con retinoblastoma bilateral. Reporte de caso y revisión de la literatura / Benign pineal gland cyst in a patient with bilateral retinoblastoma. Case report and literature review

Introducción: Los pacientes con Retinoblastoma (RB) hereditario se encuentran en riesgo de desarrollar otros tipos de tumores malignos primarios extraoculares durante la vida. Dentro de estos tumores se encuentra el pinealoblastoma, un tipo de neoplasia maligna que aparece en la glándula pineal y que se puede desarrollar en cualquier momento del diagnóstico del retinoblastoma bilateral. Objetivo: Presentar un caso inusual de retinoblastoma (RB) hereditario tratado y en remisión quien desarrolló un quiste pineal benigno. Diseño del estudio: Reporte de caso y revisión de literatura. Resumen del caso: Presentamos un paciente con diagnóstico de RB hereditario tratado y en remisión quien desarrolló un quiste pineal benigno durante el seguimiento clínico. Las lesiones quísticas de la glándula pineal reportadas por resonancia magnética son infrecuentes en edad pediátrica, sin embargo, su incidencia se ve aumentada en pacientes con RB, lo que genera incertidumbre sobre la posibilidad de presentar una neoplasia maligna. Aún se desconoce el mecanismo fisiopatológico de la aparición de quistes de la glándula pineal en pacientes con RB hereditario, pero podría tener relación con la alteración genética o con el tratamiento quimioterápico que reciben los pacientes para el tumor primario intraocular. Conclusión: Las características imagenológicas son fundamentales para diferenciar entre lesiones benignas y malignas de la glándula pineal en pacientes con retinoblastoma hereditario y para hacer el estrecho seguimiento junto con el examen clínico.

Background: Patients with hereditary Retinoblastoma (RB) are at risk of developing other types of extraocular primary malignancies throughout life. Among these tumors, pinealoblastoma is a type of malignancy that appears in the pineal gland and can develop at any time from the diagnosis of bilateral retinoblastoma. Objective: To present an unusual case of a patient with a diagnosis of hereditary BR who developed a pineal cyst. Study design: Case report. Case summary: We present in this article the case of a patient with a diagnosis of hereditary BR with remission who developed a pineal cyst during clinical follow-up. The cystic lesions of the pineal gland reported by magnetic resonance are infrequent in pediatric age, however its incidence is increased in patients with RB, which generates uncertainty about the possibility of the development of a primary pineal gland malignancy. The pathophysiological mechanism of pineal gland cysts in patients with hereditary RB is still unknown, but it could be related to a genetic alteration or to chemotherapy treatment that these patients receive for the primary intraocular tumor. Conclusion: The imaging characteristics are fundamental to differentiate between benign and malignant lesions of the pineal gland in patients with Hereditary Retinoblastoma and to make a close follow up.

Modeling Developmental and Tumorigenic Aspects of Trilateral Retinoblastoma via Human Embryonic Stem Cells.

Human embryonic stem cells (hESCs) provide a platform for studying human development and understanding mechanisms underlying diseases. Retinoblastoma-1 (RB1) is a key regulator of cell cycling, of which biallelic inactivation initiates retinoblastoma, the most common congenital intraocular malignancy. We developed a model to study the role of RB1 in early development and tumor formation by generating RB1-null hESCs using CRISPR/Cas9. RB1-/- hESCs initiated extremely large teratomas, with neural expansions similar to those of trilateral retinoblastoma tumors, in which retinoblastoma is accompanied by intracranial neural tumors. Teratoma analysis further revealed a role for the transcription factor ZEB1 in RB1-mediated ectoderm differentiation. Furthermore, RB1-/- cells displayed mitochondrial dysfunction similar to poorly differentiated retinoblastomas. Screening more than 100 chemotherapies revealed an RB1-/--specific cell sensitivity to carboplatin, exploiting their mitochondrial dysfunction. Together, our work provides a human pluripotent cell model for retinoblastoma and sheds light on developmental and tumorigenic roles of RB1.

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.

Magnetic resonance imaging based morphologic evaluation of the pineal gland for suspected pineoblastoma in retinoblastoma patients and age-matched controls.

PURPOSE: The purpose of this study was to evaluate the morphologic magnetic resonance imaging (MRI) characteristics of the pineal gland in retinoblastoma (Rb) patients without and with pineoblastoma in comparison to age-matched controls to improve early identification of pineoblastomas (trilateral retinoblastoma, TRb). METHODS AND MATERIALS: 80 patients with retinoblastoma and 80 age-matched controls who had undergone brain MRI were included in this retrospective institutional review board approved cohort study. Two readers analyzed the following MR characteristics of the pineal gland: signal intensity on T1- and T2-weighted images, enhancement pattern, delineation of the gland, presence of cystic component, size of pineal gland and size of pineal cysts, respectively. A third reader assessed all images for the presence or absence of pineoblastoma. RESULTS: 3 patients were positive (TRb cohort) and 77 negative for pineoblastoma (non-TRb cohort). The mean maximum diameter of the pineal gland was 6.4mm in Rb patients and 6.3mm in age-matched controls. The mean volume of the pineal gland in Rb patients was 93.1mm(3) and was 87.6mm(3) in age-matched controls. Considering all available MRI scans the mean maximum diameter of the pineal gland in TRb patients was 11.2mm and the mean volume in TRb patients was 453.3mm(3). The third reader identified pineoblastomas with a sensitivity of 100% (3 of 3) and a specificity of 94% (72 of 77). CONCLUSION: Our non-TRb patients did not show significant differences in the size of the pineal gland and pineal gland cysts compared to age-matched controls. The presented data can serve as a reference for the volume of normal pineal glands and pineal cysts in the diagnostic work-up of Rb patients with suspected pineoblastoma.

Baseline central nervous system magnetic resonance imaging in early detection of trilateral retinoblastoma: pitfalls in the diagnosis of pineal gland lesions.

BACKGROUND: Trilateral retinoblastoma (TRB) is a rare disease associating bilateral retinoblastoma (RB) with primitive intracranial neuroblastic tumor. AIM: To verify the occurrence of TRB in a single-Center case series and point out the clinical relevance of a baseline brain magnetic resonance imaging (MRI) in RB, focusing on pineal gland lesions. PATIENTS AND METHODS: Baseline MRI was routinely performed in all cases of RB from 1999. All MRIs were reviewed for this study and the RB database was checked in order to identify patients characteristics, treatments and follow-up. RESULTS: A total of 107 patients with RB were diagnosed between 1999 and 2012. Sixty-two patients had unilateral RB and 45 bilateral RB. MRI revealed the presence of pineal gland lesions in 10 patients (9%); seven were considered pineal benign cysts (6.5%), while in three patients (2.8%), TRB was suspected. All patients with TRB presented hereditary RB. In one patient, the suspected TRB was metachronous and in the other two patients was synchronous. Biopsy was not performed. Cerobrospinal fluid (CSF) was negative in all patients. The MRI modification, before treatment in the first case and later in the second case, confirmed the TRB diagnosis. The third patient died due to progressive Central Nervous System (CNS) disease that clearly confirmed the TRB diagnosis. None of the three patients had received prior chemotherapeutic treatment. DISCUSSION: TRB represents a rare condition in this series, occurring in three (2.8%) out of all patients with RB. A synchronous presentation with small lesion seems more frequent when a baseline MRI is performed. When a histologically-proven diagnosis is not available, a suspected diagnosis should be considered with caution and only follow-up will confirm the diagnosis. A wait-and-see approach should be considered.

Rare case of trilateral retinoblastoma with spinal canal drop metastasis detected with fluorine-18 fluorodeoxyglucose positronemission tomography/computed tomography imaging.

Trilateral retinoblastoma (TRb) is a rare syndrome associating hereditary bilateral or unilateral retinoblastoma (Rb) with an intracranial neuroblastic tumor. The latter arises in the midline, most often in the pineal gland, less frequently in the suprasellar or parasellar region. The outcome is usually fatal because of secondary spinal dissemination. We report 10-year-old boy presented with a right eye proptosis and leukocoria, and the magnetic resonance imaging (MRI) showed right orbital mass lesion infiltrating optic nerve and diagnosis of retinoblastoma was made. He was referred for fluorodeoxyglucose-positron emission tomography/computed tomography (FDG PET/CT) to find out the extent of the disease. PET/CT showed abnormal FDG-uptake within right orbital mass lesion, suprasellar enhancing lesion and drop metastasis in the cervical spinal canal level. He was diagnosed as a case of TRb with spinal canal drop metastasis. He underwent chemotherapy and craniospinal irradiation.

Two novel cases of trilateral retinoblastoma: genetics and review of the literature.

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.