Retinoblastoma

Retinoblastoma

1. RETINOBLASTOMA Dr. Pavan Naik

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. 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. EPIDEMIOLOGY Cumulative lifetime incidence-1 in 15000 Annual incidence –highest in first few months of life Y early incidence decreases steadily Extremely low by 6 years of age. R arely 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. Frequency is shown as a function of age at diagnosis in subgroups of unilateral versus bilateral disease.

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. 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. 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. In germinal retinoblastoma- at least one normal allele must be lost or inactivated prior to the first mitotic division of embryogenesis S perm 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. For retinoblastoma to occur both the allels have to be deleted If only one allel is deleted it is called 13q deletion syndrome

11. In germinal mutaion , which is inherited , First hit occurs before fertilisation & affects all types of cell 2 nd hit occurs in somatic retinal cells leads to RB. 2 nd 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 2 nd ry tumours …

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. 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.

14. CLINICAL MANIFESTATIONS MANIFESTATION PERCENTAGE LEUCOCORIA 56% STRABISMUS 20% RED PAINFUL EYE 7% POOR VISION 5% ASYMPTOMATIC 3% ORBITAL CELLULITIS 3% UNILATERAL MYDRIASIS 2% HETEROCHROMIA IRIDID 1% HYPHEMA 1%

15. CLINICAL MANIFESTATIONS 9 . Proptosis of eye

16. LEUCOCORIA

17. PATTERNS OF GROWTH

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. 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. 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

21. ROUTES OF SPREAD

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. Typical appearance of intraretinal retinoblastoma. Opaque, yellow-white macular tumor fed and drained by dilated, tortuous retinal blood vessels.

24. RETINOMA -spontaneously arrested retinoblastoma Limited vascularity Greyish-white Speckled Surrounding chorio -retinal atrophy RPE hypertrophy

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 P hotoreceptor 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. 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 a fenestrated membrane

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 Focal patches of myelinated retinal nerve fiber

28. LEUCOCORIA

29. TO BE CONTINUED IN NEXT CLASS STAGING DAIGNOSIS TREATMENT

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. B-scan ultrasonography of retinoblastoma. Solid, posterior intraocular mass contains strong particulate reflections attributable to intralesional calcification . 

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. 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. Computed tomography of bilateral intraocular retinoblastoma. Intraocular masses appear bright because of intralesional calcification. 

35. FFA Not usually performed Rapid filling of feeder vessel- intraretinal vasculature-draining of efferent vein Intralesional capillaries-leak fluoroscein

36. SYSTEMIC EVALUATON G erminal 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. S arcomas 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. S yndrome of multiple congenital anomalies attributed to a major deletion ( 13q deletion syndrome by karyotype analysis.

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. 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. 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. STAGING

42. PROGNOSTIC FACTORS

43. MANAGEMENT Primary goal-save life Salvage of the organ and function-secondary and tertiary Multidisciplinary approach Individualised –depends on Age Laterality Location Staging Systemic condition Overall progression Cost effectiveness

44. Current suggested protocol A Intraocular tumor- international classification group-A-C U/L or B/L Focal- cryotherapy / transpupillary thermotherapy tumors<3mm in visually non crucial areas Standard 6 cycle chemoreduction and focal therapy for larger tumors and in visually crucial areas Defer focal therapy for 6 cycles for tumors in macular and juxtapapillary areas- transpupillary thermotherapy/plaque RT in juxtapapillary and macula Focal therapy small residual tumors, plaque RT, EBRT -> 12 months.large.B /L and enucleation if U/L

45. B. Intraocular tumor, Group D U/L or B/L High dose chemotherapy/aggressive focal therapy Periocular carboplatin –vitreous seeds Primary enucleation -U/L- esp with no visual prognosis

46. C. Group E U/L or B/L Primary enucleation Evaluate histopathology for high risk factors

47. D. High risk factors on HPE- Stage 2 Baseline systemic evaluation for metastasis Standard 6 cycle adjuvant therapy High dose adjuvant chemotherapy + orbital EBRT- with scleral infiltration, extraocular extension, optic nerve extension

48. E. Extraocular tumor-Stage 3A Baseline systemic evaluation for metastases High dose chemotherapy-3-6 cycles followed by enucleation /extended enucleation , EBRT, high dose chemo 12 cycles

49. F. Regional LN metastasis Stage 3B Baseline evaluation for systemic metastasis Neck dissection, high dose chemotherapy for 6 cycles, followed by EBRT and high dose chemotherapy-12 cycles

50. G. Hematogenous /CNS metastasis-Stage 4 Palliative therapy High dose chemotherapy –BM rescue High dose chemotherapy- intrathecal chemotherapy for CNS metastases

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. CHEMOTHERAPY Chemotherapy is currently the primary therapeutic option -bilateral retinoblastoma. I nitial treatment - unilateral disease - affected eye is salvageable. M ost 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. C yclic treatment every 3–4 weeks for six or more cycles. Most intraocular retinoblastoma lesions (including intravitreal and subretinal seeds) regress substantially within the first two cycles

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.   Chemotherapy for retinoblastoma. (A) Pretreatment appearance of macular retinoblastoma. (B) Same lesion after two cycles of chemotherapy using vincristine, etoposide , and carboplatin. 

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. 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. 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. 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. Orbital implants

60. EXTERNAL BEAM RADIOTHERAPY M ost commonly employed regional eye-preserving therapy for this disease was external beam radiation therapy U sing 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 . T ype I -Calcific avascular mound Type II- prominent calcification gray-tan fish flesh appearance

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. SIDE EFFECTS OF EBRT Cataract-PSCC (6 months after radiation) Dry eye Radiation neuropathy Neovascular glaucoma Orbital bone growth arrest Non retinoblastoma malignancies

63. Plaque radiation therapy L arge 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 , P laque 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. 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. <16mm basal diameter, < 8 mm thickness Notched plaque to protect optic nerve To apex-4000-5000cGy Sutured to sclera, left in situ-36-72hrs

66. A.PRETREATMENT MACULAR RETINOBLASTOMA B.POST PLAQUE RT-REGESSED

67. Ruthenium plaque sutured to sclera

68. LASER THERAPY PHOTOCOAGULATION TRANS-PUPILLARY THERMOTHERAPY

69. photocoagulation In photocoagulation , an argon green laser- instantaneous pronounced whitening of the target tissues .(4mmx2mm) A n indirect ophthalmoscope delivery system and relatively long exposure durations ( 1 second or more up to a continuous exposure). O phthalmologist first creates an intense confluent white chorioretinal coagulation approximately 1–2 mm wide entirely around the retinal tumor. S upplementally treats any feeding retinal blood vessels until they appear to be occluded. T reats the tumor directly until it also appears homogeneously and intensely white.

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. 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. cryotherapy Trans-scleral cryotherapy is an obliterative focal treatment -destroys targeted intraocular tissues by means of freezing I nsulated 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. 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. SIDE EFFECTS Transient RD Retinal tear

75. Course & outcome

76. references Yanoff Textbook of Ophthalmology 3 rd edition-887-894 Retinoblastoma AIOS series No 25 Indian journal of ophthalmology-April 2012

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