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Retinitis pigmentosa
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  1. 1. RETINOBLASTOMA Dr. Pavan Naik
  2. 2. HISTORY  First mentioned by Petras Pawius in Amsterdam -1597.  James Wardrop- scottish surgeon first recommended enucleation for saving lives - 1809.  Verhoeff -origin from undifferentiated retinal cells, named retinoblastoma in 1900’s.  American Ophthalmology Society first adopted the term retinoblastoma in 1926.
  3. 3. INTRODUCTION  Primary malignant neoplasm of the retina that arises from immature retinal cells  It is the most common primary intraocular malignancy of childhood in all racial groups  Seventh MC tumor of childhood  Unifocal/multifocal.  Unilateral (70%) or bilateral (30%).  Sporadic (94%) or familial (6%).  Non hereditary (50-60%) or hereditary (40- 50%).
  4. 4. EPIDEMIOLOGY  Cumulative lifetime incidence-1 in 15000  Annual incidence –highest in first few months of life  Yearly incidence decreases steadily  Extremely low by 6 years of age.  Rarely diagnosed congenitally or even within the first 3 months of life, except in familial cases.  Median age at the time of diagnosis is approximately 12 months  B/l retinoblastoma (12 months )>18m in u/l case  Retinoblastoma affects boys and girls with equal frequency and has no known racial predilection.
  5. 5. Frequency is shown as a function of age at diagnosis in subgroups of unilateral versus bilateral disease.
  6. 6. INHERITANCE  60–70% of retinoblastoma – unilateral  30–40% are bilateral.  In unilateral cases, only a single tumor is usually present in the affected eye.  In bilateral cases, multifocal tumors in both eyes are the rule. Retinoblastoma is generally a sporadic condition (i.e., no previously affected family members exist).
  7. 7.  Sporadic form of retinoblastoma are affected unilaterally.  A small number -have a prior family history of retinoblastoma-one of the parents is probably a survivor of the disease.  Transmission of the disease in such families follows genetic rules of autosomal dominant inheritance.
  8. 8. GENETICS  Loss or inactivation of both normal alleles of the retinoblastoma gene  DNA sequence localized to a small segment of the long arm (the q14 region) of chromosome 13  The timing of the loss or inactivation of the two normal alleles  germinal (i.e., can be inherited by the offspring of an affected person)  somatic (i.e., cannot be inherited by the offspring of an affected person)
  9. 9.  In germinal retinoblastoma- at least one normal allele must be lost or inactivated prior to the first mitotic division of embryogenesis  Sperm or the egg contains defective DNA from an affected or carrier parent or develops that defect by means of spontaneous mutation prior to fertilization.  In somatic retinoblastoma, both alleles are present and active beyond the stage of the fertilized egg- but subsequent mutations occur to delete or inactivate both alleles in at least one immature retinal cell (retinoblast).
  10. 10. For retinoblastoma to occur both the allels have to be deleted  If only one allel is deleted it is called 13q deletion syndrome
  11. 11.  In germinal mutaion , which is inherited ,  First hit occurs before fertilisation & affects all types of cell  2nd hit occurs in somatic retinal cells leads to RB.  2nd ry tumours like osteosarcoma are seen in familial cases  But in sporadic mutation both hits occurs during development of retina , so it affects only retina , no 2nd ry tumours…
  12. 12. Individuals who inherit a mutation in the retinoblastoma gene are heterozygous for the mutation in all cells of the body. The “second hit” to the remaining normal copy of the gene occurs in a developing retinal cell and leads to tumor formation
  13. 13. MOLECULAR PATHOGENESIS  RB1 protein: cell cycle regulator, checkpoint between G1 & S-phase.  Key factor in RB protien functioning is the phosphorylation status.  Normally unphosphorylated and suppresses entry into S- phase by binding to E2F (transcription apparatus).  Phosphorylation by cyclin/cdk’s abolishes inhibition & causes dissociation of E2F which binds to DNA & promotes progression through cell cycle.
  15. 15. CLINICAL MANIFESTATIONS 9. Proptosis of eye
  16. 16. LEUCOCORIA
  18. 18. CLINICAL MANIFESTATIONS  Clinical presentation depends on the stage of the disease  Early likely to be missed- unless IDO is performed  Translucent white fluffy retinal mass  Strabismus- if tumor involves macula/reduced visual acuity  Moderately advanced-leucocoria reflection of light by white mass in the fundus
  19. 19. THREE MANIFESTATIONS  Endophytic: grows in to vitreous cavity. Yellow white mass fills vitreous cavity & vitreous seeds. Retinal vessels –not seen on the surface  Exophytic: tumor towards subretinal space. Retinal detachment, retinal vessels are seen over tumor  Diffuse infiltrating tumor: diffusely involve retina placoid thickness of the retina. Older children delay in diagnosis
  20. 20.  Advanced- proptosis secondary to optic nerve/ orbital extension  Orbital extension-scleral emissary veins  Atypical manifestations: -pseudohypopyon -spontaneous hyphema -vitreous hemorrhage -phthisis bulbli -preseptal/orbital cellulits
  22. 22. PRESENTATION  White round oval dome shaped retinal masses  Attract retinal BVs  Very small tumors - Translucent thickenings  Larger tumors- non rhegmatogenous RD  Tumors – extend via RPE- exophytic - into vitreous - endophytic -generalised thickening-Infiltrating Retinoblastoma  Ocassionally stops progressing-Retinoma  Severe necrosis-Phthisis
  23. 23. Typical appearance of intraretinal retinoblastoma. Opaque, yellow-white macular tumor fed and drained by dilated, tortuous retinal blood vessels.
  24. 24. RETINOMA-spontaneously arrested retinoblastoma Limited vascularity Greyish-white Speckled Surrounding chorio-retinal atrophy RPE hypertrophy
  25. 25. PATHOLOGY  Malignant neuroepithelial cells (retinoblasts)- arise within the immature retina  The retinoblasts -large basophilic nucleus and scanty cytoplasm.  Cellular necrosis & intralesional calcification- larger tumors.  Tissue differentiation occurs,- producing Flexner-Wintersteiner rosettes or Homer Wright rosettes  Photoreceptor differentiation of individual retinoblasts (fleurettes) may also be observed  Retinoblastoma - tendency to invade the optic nerve and choroid - extend out of the globe via either the optic nerve or the scleral emissary canals.  Retinomas show such tumors to be composed entirely of benign- appearing neuronal cells with photoreceptor differentiation, most notably in the form of fleurettes.  Pseudorosettes-tumor cells around Blood vessels
  26. 26. PATHOLOGY Flexner Wintersteiner rosettes -columnar cells around a central lumen -also seen in medulloepithelioma Homer Wright -rosettes around a central neuromuscular core -neuroblastoma, medulloepithelioma, medulloblastomas Fleurettes Tumor cells with pear shaped eosinophilic processes projecting through
  27. 27. DIFFERENTIAL DIAGNOSIS Differential Diagnosis of Leukokoria Coats’ disease Persistent hyperplastic primary vitreous Ocular toxocariasis Cicatricial retinopathy of prematurity Familial exudative vitreoretinopathy Incontinentia pigmenti retinopathy Norrie’s disease Differential Diagnosis of Vitreous Seeds Pars planitis (intermediate uveitis) Microbial endophthalmitis or retinitis Leukemic infiltration Differential Diagnosis of Discrete Retinal Tumors Astrocytoma of retina Medulloepithelioma Retinal capillary hemangioma
  28. 28. LEUCOCORIA
  30. 30. DIAGNOSIS  ULTRASONOGRAPHY  >10-15mm, multiple foci of calcification  Shadows the sclera & orbital soft tissue  On reducing the gain-reflection persist  Demonstrates a mass more echogenic than vitreous on B scan highly reflective intrinsic echoes of fine calcifications-Ascan  RD in exophytic tumors  Accuracy-80% limited by vitreous opacities & RD  Limited evaluation of medial and lateral extension  Colour Doppler: displays normal & tumor vasculature & differentiates subretinal or choroidalh’he from neoplasms
  31. 31. B-scan ultrasonography of retinoblastoma. Solid, posterior intraocular mass contains strong particulate reflections attributable to intralesional calcification.
  32. 32. INDIRECT OPHTHALMOSCOPY  Dilated fundus examination under anaesthesia  IOP and anterior segment-neovascularisation, pseudohypopyon, hyphema and signs of inflammation  Bilateral fundus examination-360◦ scleral depression  Ret Cam: wide angle fundus camera –documenting and monitoring response
  33. 33. CT SCAN  Bright on CT scan  Infiltrating Retinoblastoma-tumor multicentricity , extensive seeding into vitreous MRI  Most useful for evaluating sellar/parasellar  Rule out- ectopic intracranial RB  Studying optic nerve & soft tissues
  34. 34. Computed tomography of bilateral intraocular retinoblastoma. Intraocular masses appear bright because of intralesional calcification.
  35. 35. FFA  Not usually performed  Rapid filling of feeder vessel-intraretinal vasculature- draining of efferent vein  Intralesional capillaries-leak fluoroscein
  36. 36. SYSTEMIC EVALUATON  Germinal retinoblastoma have a strong tendency to develop non-retinoblastoma malignancies  Primary nonretinoblastoma intracranial malignancy - either a pineoblastoma or an ectopic intracranial retinoblastoma- most common neoplasm -somnolence, headache, and other neurological symptoms.  Central nervous system -solid tumor that involves the suprasellar or parasellar regions of the brain  Ophthalmoscopy frequently reveals papilledema- referred to as trilateral retinobloma, seed the cerebrospinal fluid and thereby spawn implantation tumors along the spinal cord. This malignancy is usually fatal
  37. 37. Sarcomas of bone and soft tissues- most frequent nonretinoblastoma malignancies Oculo-orbital external beam radiation therapy- < age of 1 year appears-increase the likelihood that such tumors will occur in the field. Syndrome of multiple congenital anomalies attributed to a major deletion (13q deletion syndrome by karyotype analysis.
  38. 38. BASELINE SYSTEMIC EVALUATION IN RETINOBLASTOMA  Complete pediatric history and physical examination  Blood for complete blood count (CBC)  MRI or CT of brain, especially in bilateral or familial cases to look for ectopic intracranial retinoblastoma  Lumbar puncture for cerebrospinal fluid analysis[∗]  Bone marrow aspiration or biopsy[∗]  Bone scan[∗]
  39. 39. INTERNATIONAL CLASSIFICATION (SHIELDS)  Group A Small tumor Retinoblastoma <3mm in size in basal dimension/thickness  Group B Larger tumor Retinoblastoma>3mm basal diameter/ thickness Macular location<3mm to foveola Juxtapapillary location <1.5mm to the disc Clear subretinal fluid<3mm from the margin  Group C Focal seeds c1-subretinal seeds<3mm c2 –vitreous seeds <3mm c3-both subretinal and vitreous seeds
  40. 40.  Group D Diffuse seeds D1-subretinal seeds>3mm D2-vitreous seeds >3mm D3-Both  Group E Extensive Retinoblastoma occupying>50% of the globe neovascular glaucoma opaque media-hhge- AC/PC/Subretnal space Invasion of postlaminar optic nerve/ choroid/sclera/orbit/AC
  41. 41. STAGING
  43. 43. MANAGEMENT  Primary goal-save life  Salvage of the organ and function-secondary and tertiary  Multidisciplinary approach  Individualised –depends on 1. Age 2. Laterality 3. Location 4. Staging 5. Systemic condition 6. Overall progression 7. Cost effectiveness
  44. 44. CURRENT SUGGESTED PROTOCOL  A Intraocular tumor- international classification group-A-C U/L or B/L 1. Focal-cryotherapy/transpupillary thermotherapy tumors<3mm in visually non crucial areas 2. Standard 6 cycle chemoreduction and focal therapy for larger tumors and in visually crucial areas 3. Defer focal therapy for 6 cycles for tumors in macular and juxtapapillary areas-transpupillary thermotherapy/plaque RT in juxtapapillary and macula 4. Focal therapy small residual tumors, plaque RT, EBRT -> 12 months.large.B/L and enucleation if U/L
  45. 45.  B. Intraocular tumor, Group D U/L or B/L 1. High dose chemotherapy/aggressive focal therapy 2. Periocular carboplatin –vitreous seeds 3. Primary enucleation-U/L- esp with no visual prognosis
  46. 46.  C. Group E U/L or B/L 1. Primary enucleation 2. Evaluate histopathology for high risk factors
  47. 47.  D. High risk factors on HPE- Stage 2 1. Baseline systemic evaluation for metastasis 2. Standard 6 cycle adjuvant therapy 3. High dose adjuvant chemotherapy + orbital EBRT- with scleral infiltration, extraocular extension, optic nerve extension
  48. 48.  E. Extraocular tumor-Stage 3A 1. Baseline systemic evaluation for metastases 2. High dose chemotherapy-3-6 cycles followed by enucleation/extended enucleation, EBRT, high dose chemo 12 cycles
  49. 49.  F. Regional LN metastasis Stage 3B 1. Baseline evaluation for systemic metastasis 2. Neck dissection, high dose chemotherapy for 6 cycles, followed by EBRT and high dose chemotherapy-12 cycles
  50. 50.  G. Hematogenous /CNS metastasis-Stage 4 1. Palliative therapy 2. High dose chemotherapy –BM rescue 3. High dose chemotherapy- intrathecal chemotherapy for CNS metastases
  51. 51. TREATMENT  TREATMENT OPTIONS FOR INTRAOCULAR RETINOBLASTOMA Intravenous chemotherapy Enucleation Radiation therapy • External beam radiation therapy • Plaque radiotherapy Laser therapy • Photocoagulation • Transpupillary thermotherapy (TTT) Cryotherapy Observation (for spontaneously arrested retinoblastoma, retinoma)
  52. 52. CHEMOTHERAPY  Chemotherapy is currently the primary therapeutic option -bilateral retinoblastoma.  Initial treatment - unilateral disease -affected eye is salvageable.  Most common chemotherapeutic regimen -a combination of carboplatin, etoposide or a related drug, and vincristine (CEV regimen). In some centers, cyclosporine is added to this regimen to reduce the multidrug resistance that occurs in many retinoblastomas.  Chemotherapy must be supervised by a pediatric oncologist who is familiar with the side effects and complications of the drugs and can monitor the child closely during treatment.  Cyclic treatment every 3–4 weeks for six or more cycles.  Most intraocular retinoblastoma lesions (including intravitreal and
  53. 53.  Partially regressed tumors -still viable following the second cycle of chemotherapy / any new tumors during the course of chemotherapy must be treated by obliterative local therapies such as cryotherapy, laser therapy, and episcleral plaque radiation therapy.  Periocular carboplatin injections are currently being evaluated as an adjunct to intravenous chemotherapy in selected cases.  Residual or recurrent intravitreal and subretinal seeds following chemotherapy and local treatments usually require external beam radiation therapy if the eye is to be salvaged.
  54. 54. Chemotherapy for retinoblastoma. (A) Pretreatment appearance of macular retinoblastoma. (B) Same lesion after two cycles of chemotherapy using vincristine, etoposide, and carboplatin.
  55. 55. ENUCLEATION  Enucleation remains an important therapeutic option for this disease.  Children who have unilateral advanced intraocular disease.  Enucleation is sometimes recommended for both eyes in children who have bilateral far-advanced disease not amenable to any eye-preserving therapy and for the more severely affected eye in markedly asymmetrical bilateral cases.  If enucleation is performed, the ophthalmic surgeon should attempt to obtain a long section of the optic nerve during surgery.
  56. 56.  The principal route of exit of tumor cells from the eye is along the optic nerve. Prior pathological studies have shown that enucleation is usually curative in retinoblastoma if an optic nerve section longer than 5 mm is obtained with the globe.[15] If possible, the ophthalmic surgeon should attempt to obtain an optic nerve section 10–15 mm long in every case.  Insertion of an orbital implant at the time of enucleation appears to be appropriate except when there is a strong likelihood of residual tumor in the orbit..
  57. 57. SPECIAL CONSIDERATIONS FOR ENUCLEATION  A Minimal manipulation  B Avoid perforation of the eye  C Harvest long >15 mm optic nerve stump  D inspect the enucleated eye for macroscopic extraocular extension & optic nerve involvement  E Harvest fresh tissue for genetic studies  F Place a primary implant  G Avoid biointegrated implant if postoperative radiotherapy is necessary
  58. 58. ORBITAL IMPLANT  Promotes orbital growth  Provides better cosmesis  Enhances prosthesis motility  Non integrated(PMMA/ silicon)  Bio integrated(hydroxyapatite/porous polyethylene)  Avoided if post operative adjuvant RT is necessary  Implant vascularisation compromised by RT  Myoconjunctival technique
  59. 59. Orbital implants
  60. 60. EXTERNAL BEAM RADIOTHERAPY  Most commonly employed regional eye-preserving therapy for this disease was external beam radiation therapy  Using a linear accelerator in a hospital radiation therapy department.  Standard target doses of radiation to the eye and orbit are in the range of 40–50 Gy given in multiple fractions of 150–200 cGy over 4–5 weeks.  External beam radiation therapy results in highly effective regression of vascularized retinal tumors.  Tumor regression have been identified.  Type I-Calcific avascular mound Type II-prominent calcification gray-tan fish flesh appearance
  61. 61.  One or more tumors which involve optic disc  Diffuse vitreal/subretinal seeding  Prior chemo/local therapy has failed  Vitreous seeds do not respond well-relatively hypoxic state
  62. 62.  SIDE EFFECTS OF EBRT  Cataract-PSCC (6 months after radiation)  Dry eye  Radiation neuropathy  Neovascular glaucoma  Orbital bone growth arrest  Non retinoblastoma malignancies
  63. 63. PLAQUE RADIATION THERAPY  Large but localized in the presence of limited localized vitreous seeding & does not involve optic disc/macula  Plaque radiation therapy -surgical implantation of a radioactive device (eye plaque) of appropriate size and strength on the sclera overlying the intraocular tumor,  Plaque in place for a sufficient period of time (usually 2–5 days) to provide a predetermined radiation dose to the apex of the tumor, and subsequent surgical removal of the plaque.
  64. 64.  The principal isotopes used in radioactive eye plaques at present are iodine-125 and ruthenium- 106.  Target dose of 40–45 Gy to the tumor apex is generally employed. As a result of the physical dose-distribution -,the base of the tumor always receives a substantially >apex.  Orbital tissue –layer of metal on outer surface shields the emission in that direction
  65. 65.  <16mm basal diameter, < 8 mm thickness  Notched plaque to protect optic nerve  To apex-4000-5000cGy  Sutured to sclera, left in situ-36-72hrs
  67. 67. Ruthenium plaque sutured to sclera
  69. 69. PHOTOCOAGULATION  In photocoagulation, an argon green laser- instantaneous pronounced whitening of the target tissues.(4mmx2mm)  An indirect ophthalmoscope delivery system and relatively long exposure durations (1 second or more up to a continuous exposure).  Ophthalmologist first creates an intense confluent white chorioretinal coagulation approximately 1–2 mm wide entirely around the retinal tumor.  Supplementally treats any feeding retinal blood vessels until they appear to be occluded.  Treats the tumor directly until it also appears homogeneously and intensely white.
  70. 70. SIDE EFFECTS  Transient serous RD  Retinal vascular occlusion  Retinal hole  Retinal traction  Pre retinal fibrosis  Large xisual field defect major complication  CI-active chemoreduction-restricts blood supply so reduces concentration of chemotherapeutic agent
  71. 71. TRANS PUPILLARY THERMOTHERAPY  Infrared laser beam 810nm  Operating microscope/IDO  Larger spot size 2-3mm  Till dull white discolouration is produced  Overlapping spots till homogenous  Tumor-replaced by chorioretinal atrophy-end point  Follow up 2-4 weeks  Extra macular or extrapapillary tumors
  72. 72. CRYOTHERAPY  Trans-scleral cryotherapy is an obliterative focal treatment -destroys targeted intraocular tissues by means of freezing  Insulated retinal cryoprobe to indent the sclera overlying the tumor and indirect ophthalmo-scopy to monitor the position of the indentation in the fundus.  Once the probe tip is positioned at the site of a retinal tumor, the ophthalmologist activates the probe to begin freezing.
  73. 73.  The ice ball that forms -encompass the entire tumor (if the tumor is small) or a portion of the tumor (if the tumor is larger) and extend into the overlying vitreous.  The probe is then deactivated, and the ice ball is allowed to thaw.  This cycle is repeated once (double freeze-thaw method) or twice (triple freeze-thaw method) at each site. If the tumor is larger than can be encompassed entirely by a single freeze, Repeated every 2-4 weeks  Cryo-applied 2-3 hours prior to chemo-increases delivery of drug across BRB
  74. 74. SIDE EFFECTS  Transient RD  Retinal tear
  75. 75. COURSE & OUTCOME
  76. 76. REFERENCES 1. Yanoff Textbook of Ophthalmology 3 rd edition-887- 894 2. Retinoblastoma AIOS series No 25 3. Indian journal of ophthalmology-April 2012
  77. 77.  THANK YOU
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