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Retinoblastoma tema de revision en pediatria.pptx
- 1. RETINOBLASTOMA Luis Fernando Visbal Salamanca Residente de Genética Médica Pontificia Universidad Javeriana
- 2. Introducción El retinoblastoma es el tumor maligno de la retina más frecuente en los niños. RB1 Origen embrionario de la retina ( fotorreceptor). Herencia autosómica dominante. 10-15% del cáncer que se presenta en el primer año de vida. 3% de todos los cánceres en menores de 15 años.
- 3. Introducción Hereditario: 40-50%. Bilateral, multifocal, historia familiar. 15% es unilateral. Tiende a ser diagnosticado de a edades mayores. Unilateral y unifocal. Retinoblastoma. Clinical presentation ,evaluation and diagnosis. Uptodate. ( 2022)
- 4. Epidemiología Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021. Incidencia de 1/16.000 a 1/18.000 En países de bajos ingresos se relacionan con un peor desenlace. Retinoblastoma. Clinical presentation ,evaluation and diagnosis. Uptodate. ( 2022)
- 5. Patogénesis RB1 pRB Regulación ciclo celular. • Unión E2F represión genes para proliferación celular. GST • Hiperfosforilación por CDKs por mitógenos libera represión promueve G1 a S Por variante no represión sin mitógenos proliferación. Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021.
- 6. Patogénesis Modelo de 2 hits de genes supresores de tumores. • Variantes bialélicas en RB1 Rb. • + cambios genéticos o epigenéticos M3 transformación maligna Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021. Hereditario • Germinal (M1) + somática (M2) No hereditario • 2 somáticas
- 7. Patogénesis Variantes somáticas • 98% RB1 M1 y M2 • Hipermetilación promotor RB1 de esporádicos, unilateral. • 1,5% amplificación MYCN tumoral de esporádicos unilateral (RB1 normal). Variantes germinales • 80-84% variantes puntuales • 25% PTC • 16-20% del/dup • 6-8% deleción 13q14+ RGD, malformaciones congénitas. Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021.
- 8. Patogénesis Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021.
- 9. Patogénesis Hereditario 45-50% de casos. • Bilateral 80% • Unilateral 15% • Trilateral 5% (pinealoblastoma) • Multifocal • > con alelos nulos. Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021. Penetrancia >99% en alelos nulos (PTC, frameshift). <10% de familias con “fenotipo de baja penetrancia” con expresividad reducida y penetrancia <25%. • Variantes in –frame, missense, splicing, indels, promotor.
- 10. Clínica Leucocoria Estrabismo (acompaña o precede leucocoria). Cambio en apariencia ocular. • Glaucoma, celulitis, uveítis, hifema, hemorragia vítrea. Disminución agudeza visual. Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021.
- 11. Clínica Los probandos con retinoblastoma presentan las siguientes características: • 60% Historia familiar negativa + Rb unilateral. • 30% Historia familiar negativa + Rb bilateral. • 10% Historia familiar positiva + Rb unilateral o bilateral. • Deleción 13q14 • 5% de unifocal • 7,5% de multifocal. • + RGD y defectos congénitos. Lanzkowsky’s Manual of Pediatric Hematology and Oncology. Séptima Edición.
- 12. Clínica Unilateral • 60% • Media diagnóstico 24 meses. • Unifocal • Grande dificulta diferenciar si solo un tumor. Bilateral • 40% • Media diagnóstico 15 meses. • Mayor compromiso al diagnóstico. • Multifocal. • Algunos tienen inicialmente diagnóstico unilateral. Trilateral • Pinealoblastoma: tumores del neuroectodermo primitivo. • 4% de las formas familiares. Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021.
- 13. Clínica Retinoma + cicatrices en retina. Ojo “ptísico” (calcificado) por regresión de Rb + oclusión vascular. Otros tumores segundos primarios. • Osteosarcomas • Sarcomas de tejidos blandos (leimoiosarcomas o rabdomiosarcomas). • Melanomas • Cáncer de pulmón. • Adolescencia o adultez. • 50% de riesgo si recibieron radioterapia. Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021.
- 14. • Más de un afectado en familiar 10%. • Solo un afectado en la familia 90%. Lohmann DR, Gallie BL. Retinoblastoma. 2000 Jul 18 [Updated 2018 Nov 21]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1452/
- 15. Diagnóstico Valoración oftalmológica (dilatación pupila). Evaluación bajo anestesia de retina completa: clasificación de severidad. No se necesita histopatología ya que aumenta el riesgo de metástasis. Imagen ocular. • Ecografía: calcificaciones. • RMN: invasión Nervio óptico y trilateral. • Evitar TC riesgo segundos primarios. Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021.
- 16. Diagnóstico Lanzkowsky’s Manual of Pediatric Hematology and Oncology. Séptima Edición.
- 17. Aerts I, et al. Orphanet J Rare Dis. 2006;1:31.
- 18. Estadificación Dimaras H, et al. Nat Rev Dis Primers. 2015;1:15021.
- 19. Diagnóstico • Estadificación para riesgo genético: • HX: individuo con evidencia insuficiente o desconocida de variante RB1 patogénica constitucional. • H0: individuo que no heredó variante patogénica germinal familiar conocida (confirmado molecularmente). • H0* individuo con Rb o retinoma sin variante patogénica germinal en RB1. Riesgo de mosaicismo <1%. • H1: individuo con Rb bilateral, trilateral, Rb + historia familiar o variante germinal patogénica en RB1. Lohmann DR, Gallie BL. Retinoblastoma. 2000 Jul 18 [Updated 2018 Nov 21]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.
- 20. Diagnóstico molecular Lohmann DR, Gallie BL. Retinoblastoma. 2000 Jul 18 [Updated 2018 Nov 21]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA):
- 21. Estudio molecular Familiares de afectado en riesgo de Rb y otros cánceres. •Determinar si variante hereditaria. •Análisis de variante en familiares en riesgo. Manejo médico inmediato en portadores de variante germinal. Mejorar pronóstico, desenlace visual, disminuir riesgos para paciente. Seguimiento portadores. Dx prenatal National Retinoblastoma Strategy Canadian Guidelines for Care: Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44 Suppl 2:S1-88.
- 22. Clasificación de riesgo Pre-test. Skalet AH, et al. Ophthalmology. 2018;125(3):453-8.
- 23. Skalet AH, et al. Ophthalmology. 2018;125(3):453-8.
- 24. Seguimiento Skalet AH, et al. Ophthalmology. 2018;125(3):453-8.
- 25. Manejo Se recomienda que se realice en centros con experiencia Objetivos terapéuticos: • Preservación de la vida del niño • Preservación de la vista. • Evitar radioterapia en pacientes con Rb hereditario. Es un manejo multidisciplinario. Lohmann DR, Gallie BL. Retinoblastoma. 2000 Jul 18 [Updated 2018 Nov 21]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1452/
- 26. Manejo 1. Enucleación: se recomienda en estadios avanzados ( E) cuando ya no hay probabilidad de preservación de la vista. Ha disminuido con el tiempo. Puede requerir quimioterapia como adyuvancia. 2. Terapias oculares focales: Crioterapia y láser • Láser: tumores < 4.5 mm de base y < 2.5 mm in grosor sin compromiso del vítreo. • Crioterapia: tumores pequeños ( 2-3 mm de diámetro) los congela a -80C con la formación de hielo intracelular que destruye la membrana tumoral. 3. Quimioterapia sistémica: lo más utilizado e nivel mundial. Carboplatino o vincristina. Puede requerir también terapias focales (crioterapia o láser). 4. Radiación con placas epiesclerales o radioterapia de haz externo.
- 27. Seguimiento • H1 • Evaluación bajo anestesia c/3-4 semanas hasta 6meses, luego c/m hasta 3 años c/3-6m hasta 7 años cada año – 2 años posterior. • H0* Seguimiento clínico + ecografía • Retinoma seguimiento clínico + imagen c/1-2 años. • RMN corporal total para portadores de variantes germinales en investigación. Lohmann DR, Gallie BL. Retinoblastoma. 2000 Jul 18 [Updated 2018 Nov 21]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews.
- 28. GRACIAS
Notas del editor
- 27 exones 928 aa RB1 encodes a ubiquitously expressed nuclear protein that is involved in cell cycle regulation (G1 to S transition). The RB protein is phosphorylated by members of the cyclin-dependent kinase (cdk) system prior to the entry into S-phase. On phosphorylation, the binding activity of the pocket domain is lost, resulting in the release of cellular proteins.
- Nature Reviews | Disease Primers Figure 3 | Genetic origins of retinoblastoma. Three genetic subtypes of retinoblastoma are known. Patients with heritable retinoblastoma have a constitutive inactivating mutation (mutation 1 (M1)) in the tumour‑suppressor retinoblastoma gene (RB1) in all cells of their body. A second, somatic mutation (M2) in a susceptible retinal cell can lead to benign retinoma. Further genetic and/or epigenetic events (M3 … Mn) are required to transform the retinoma into retinoblastoma. Non-heritable RB1 −/− retinoblastomas progress similarly, except that both M1 and M2 occur in one susceptible retinal cell. RB1 +/+ MYCN-amplified (RB1 +/+ MYCN A ) retinoblastoma is a rare, non-heritable retinoblastoma subtype driven by amplification of MYCN with normal RB1; other changes in these tumours remain uncharacterized. Histological analysis of retinomas shows distinct photoreceptor-like fleurettes, whereas RB1 −/− retinoblastoma can show Flexner–Wintersteiner and Homer Wright rosettes (not shown). RB1 +/+ MYCN A retinoblastomas have a distinct morphology, with rounded nuclei and prominent nucleoli related to the high levels of MYCN. BCOR, BCL‑6 co‑repressor; CDH11, cadherin 11; KIF14, kinesin family member 14; RBL2, retinoblastoma‑like 2; SYK, spleen tyrosine kinase. igure 1. Schematic of the molecular genetic mechanisms that result in non-heritable and heritable retinoblastoma. The development of retinoblastoma is initiated if both RB1 alleles are mutated. In non-heritable retinoblastoma, both pathogenic variants (first and second variant) occur in somatic cells (somatic variants). Note: The pathogenic variants are not detected (two normal alleles, RB RB) in DNA from constitutional cells (e.g., from peripheral blood). In heritable retinoblastoma, only the second mutation is a somatic event. Independent second pathogenic variants give rise to independent tumor foci (multifocal retinoblastoma tumors). The first pathogenic variant is inherited via the germline (either a de novo germline variant or a pathogenic allele inherited from a parent). Note: In constitutional cells, the affected individual is heterozygous (RB rb) for the mutated allele. In some affected individuals the first pathogenic variant has occurred during embryonal development. Note: The affected individual is somatic mosaic for the first pathogenic variant. Tumors may develop from cells that belong to the mutated sector stemming from the cell in which the first pathogenic variant has occurred. In addition to loss of RB1, specific alterations in copy number of other genes are common in RB1 -/- retinoblastoma. There are gains (4‒ 10 copies) in oncogenes MDM4, KIF14 (1q32), MYCN (2p24), DEK, and E2F3 (6p22) and loss of the tumor suppressor gene CDH11 (16q22-24). Could We have dIsCoveRed RetInoblastoma eaRlIeR? 3,37 Other less common genomic alterations in retinoblastoma tumors include differential expression of specific microRNAs, 38 recurrent single nucleotide variants/insertion-deletions in the genes BCOR and CREBBP, 39 and upregulation of spleen tyrosine kinase (SYK).
- Figure 1 | Progression of retinoblastoma. a | Anatomical features of a healthy eye. Genomic damage (indicated by a lightning bolt) leads to mutation of the retinoblastoma gene (RB1), resulting in biallelic functional loss of RB1 in a developing retinal cell (possibly a cone photoreceptor precursor cell that is dependent on retinoblastoma protein (pRB) to stop proliferation). b | Genomic instability leads to the formation of a benign retinoma; only 5% of patients have retinoma without retinoblastoma. Inset shows a small retinoma that is not visible except by optical coherence tomography. c | Intraretinal retinoblastoma arises as additional genomic changes promote uncontrolled cell proliferation; the tumour grows and seeds become independent, floating under the retina and into the vitreous. d | Retinoblastoma can invade adjacent tissues, such as the optic nerve, uvea or sclera, which constitutes a high-risk pathological feature. Eventually, retinoblastoma can extend extraocularly into the orbit and metastasize, especially to the bone marrow, or into the brain (direct or via the cerebrospinal fluid (CSF)).
- cFigure 5 | Online diagnosis of retinoblastoma. Detection of photoleukocoria (white pupil) on this digital image led the parents to the diagnosis of retinoblastoma. The left eye was determined by examination under anaesthesia (EUA) to have International Intraocular Retinoblastoma Classification (IIRC)79 Group D retinoblastoma and was enucleated 2 days later; a CT scan was scheduled to check for trilateral tumour. Today, MRI would be recommended to reduce radiation exposure. The pathological examination of the eye showed no high-risk features. The other eye was normal at diagnosis, but on the next examination a small tumour was detected and treated with only laser therapy (part a). One month after surgery, the child presented with high intracranial pressure. A large intracranial midline tumour (trilateral disease) was diagnosed on CT scan (arrow). The tumour was treated with chemotherapy, high-dose chemotherapy with haematopoietic rescue by stem cell transplantation, and intrathecal chemotherapy injections (directly into the cerebrospinal fluid) through an implanted intraventricular catheter (part b). Follow-up MRI at 8 years of age shows no residual disease (part c) and the child is well (part d), with one artificial eye and one eye with normal vision; he wears polycarbonate lenses to protect his only eye
- Unifocal solo un tumor id.
- Tumores de retina benigno con arresto de cre imiento espontaneo con cicatrices en retina.
- Histological examination of the retinoblastoma after enucleation of the affected eye (FIG. 3) is the only way to evaluate high-risk features (tumour invasion into the optic nerve beyond the confines of the eye or to the cut end of nerve; >3 mm of invasion of the vascular layer (choroid) under the retina; or invasion of sclera) and establish pathological staging
- by identifying children at risk prior to detection of tumours, knowledge of the RB1 mutation supports the requirement for early and aggressive tumour surveillance in order to institute early therapy to optimize outcomes. Failure to identify Rb tumours at the earliest time and smallest possible size compromises visual outcome, and increases the risk of tumours spreading beyond the eye. This is associated with a poorer outcome and requires more aggressive therapy, which is inherently associated with increased risks for the patient Prenatal diagnosis enhances early management of Rbaffected infants. Obstetrical ultrasound can visualize large intraocular Rb in the fetus as early as 33 weeks gestation
- Figure 1. Pretest risk for RB1 mutation in family members of affected child with retinoblastoma (adapted from Valenzuela et al. A Language for Retinoblastoma: Guidelines and Standard Operating Procedures. In: Pediatric Retina. Reynolds JD, Olitsky SE, eds. 2011:218). Data presented reflect the RB1 mutation detection rates based on a large data set from one of the authors (B.L.G.) of molecular genetic results for retinoblastoma patients and their family members (Racher and Gallie, unpublished data, 2017). A, All probands with bilateral disease have a constitutional mutant RB1 allele. However, the RB1 mutation is frequently de novo in the child with retinoblastoma. Thus, the majority of children with bilateral retinoblastoma are the first person in the family with disease. Before testing the patient, the risk for relatives to develop retinoblastoma can be estimated on the basis of data from a large number of families. The percentage of risk for relatives to carry the mutant allele of the proband is shown. B, Probands with unilateral disease and no family history of retinoblastoma have a 15% risk for carrying a mutant RB1 allele. The percentage of risk for relatives to carry that allele is shown. *Third- and fourth-degree relatives of unilateral probands have calculated risks of 0.003% and 0.001%, which are less than the normal population risk of 0.007% (1:15 000 live births); therefore, the risk is stated at 0.007%.
- Figure 2. Genetic testing for RB1 mutations provides clarification of risk for retinoblastoma (RB) in family members. Molecular testing identifies relatives who carry the mutant RB1 allele and are at risk for the disease. Testing can also decrease the risk for relatives to the population risk, eliminating the need for dedicated ophthalmic screening for retinoblastoma in some children, or modify the risk, allowing children to undergo less extensive screening. Genetic testing and counseling for RB is a complex issue and is best performed in coordination with genetics professionals (genetic counselors or medical geneticists) experienced in retinoblastoma. For example, although parents of a child with bilateral RB may test negative for an RB1 mutation, they still have a 5% risk with each subsequent child because of the possibility of germline mosaicism in a parent. Tumor tissue, when available, and peripheral blood lymphocytes are tested to identify mutations in RB1. Tumor tissue may not be available for testing if the child has not undergone enucleation or if frozen tumor is not available from the surgery, particularly for adult long-term survivors of RB seeking genetics evaluation. *Based on pretest risk, as described in Figure 1 and Table 1. **Calculated risk in this clinical scenario will depend on the sensitivity of the genetic testing, which varies with laboratory. The relative’s post-test risk will likely be lower than pretest risk and will result in less intense screening (Fig 3) compared with pretest risk. Geneticists experienced in RB can provide guidance in this situation. ***The risk to future offspring in this clinical scenario results from the risk that the proband is mosaic for the RB1 mutation and therefore has a risk of transmitting to offspring despite the negative blood test. Genetic testing of offspring for the RB1 mutation identified in the tumor can eliminate this risk. Before testing, these children will be followed by intermediate risk (Fig 3); however, a genetics professional can provide clarification of risk for a child according to the sensitivity of the gene testing for the parent, which varies by laboratory. When no RB1 mutation has been identified in the blood sample of the proband, genetic testing is not recommended for family members because there is no identified mutation to test for. Screening of relatives relies on the refined post-test risk estimate based on the negative results (and the sensitivity of the test of the laboratory used).
- Figure 3. Management guidelines for childhood screening for retinoblastoma. The presented schedules are general guidelines and reflect a schedule for examinations in which no lesions of concern are noted. It may be appropriate to examine some children more frequently. Decisions regarding examination method, examination under anesthesia (EUA) versus nonsedated examination in the office, are complex and best decided by the clinician in discussion with the patient’s family. The preference of the majority of the clinical centers involved in the creation of this consensus statement is reflected, but individual centers may make policy decisions based on available resources and expert clinician preference. Examination under anesthesia will be strongly considered for any child who is unable to participate in an office examination sufficiently to allow thorough examination of the retina. *A minority of clinical centers also prefer EUA for high- and intermediate-risk children (calculated risk >1%) from birth to 8 weeks of age.