Retinoblastoma

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seminar presented by Dr.Puneet Sharma ( P.G 2nd yr )
Department of Ophthalmology, MMIMSR , Mullana ( Ambala )

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Retinoblastoma

  1. 1. Presented by-Dr.Puneet Sharma Post graduate student ( 2nd yr ) Department of Ophthalmology MMIMSR,Mullana Ambala
  2. 2.  Pawius described retinoblastoma in 1597.  In 1809, wardop referred to tumor as fungus haematodes as suggested enucleation as primary mode of management.  Discovery of ophthalmoscope in 1851 facilitated reconginition of clinical features of retinoblastoma.  Thought to be derived from glial cells, was called glioma of retina by virchow (1864).  Flexner (1891) and wintersteiner (1897) believed it to be a neuroepithelioma because of presence of rosettes.  Later, consensus was that tumor originated from retinoblasts and officially american ophthalmological society (1926) accepted the term retinoblastoma.
  3. 3.  Most common intraocular malignancy in children ( 1 in 15,000 to 1 in 18,000 live births).  No racial or gender predisposition.  Bilateral in 25 to 35% cases.  Age of diagnosis is 18 months.  Unilateral cases around 24 months & bilateral before 12 months.
  4. 4.  RB gene is located on long arm of chromosome 13 (13q14) containing 27 exons & 26 introns.  2 normal copies of RB gene present in most human cells. RB gene product is 928 AA phosphoprotein whose normal func. is to suppress cell growth.  RB represents phenotypic expression of abnormal or absent tumour suppressor gene aka RB1.  Most RB1 mutations are minute deletions,
  5. 5.  Out of newly diagnosed cases  6% familial  94% sporadic  Bilateral RB involve germinal mutations  Approx. 15% unilateral sporadic RB caused by germinal mutation, affecting one eye , 85% sporadic
  6. 6.  Imp. Aspect in management of RB  Pts, positive family history, 40% siblings would be at risk & 40% offspring of affected patient may develop RB  Pts, no family history, if affected child has unilateral RB, 1% of sibilings are at risk & 8% of offspring may develop RB  Bilateral RB, no family history 6% siblings & 40% offspring have chance of developing RB
  7. 7.  On low magnification, basophilic areas of tumor are seen along with eosinophilic areas of necrosis & more basophilic areas of calcification within the tumor.  Poorly differentiated tumors consist of small to medium sized round cells with large hyperchromatic nuclei & scanty cytoplasm with mitotic figures.
  8. 8. Rosettes  Flexner-wintersteiner rosettes consist of columnar cells arranged around a central lumen,highly characteristic of retinoblastoma, also seen in medulloepithelioma.
  9. 9.  Homer wright rosettes, cells arranged around central neuromuscular tangle (neuroblastomas, medulloblastomas & medulloepitheliomas)
  10. 10.  Arrangement of tumor cells around blood vessels.
  11. 11. Fleurettes  Fleurettes -eosinophilic structures, composed of tumor cells with pear shaped eosinophilic processes, projecting through fenestrated membrane.  Basophilic deposits,precipitated DNA (released from tumor necrosis) can be found in walls of lumen of blood vessels.
  12. 12. Reese-Ellsworth classification (1960) Was designed for treatment with EBRT. Was in use till 1980 Now not used as EBRT has been replaced by chemotherapy as preferred mode of treatment
  13. 13. Group A Small tumor  R.B < 3 mm in basal dimension/thickness Group B Larger tumor  R.B > 3 mm in basal dimension/thickness  Macula location ( < 3 mm to foveola)  Juxtapapillary location ( < 1.5 mm to disc)  Clear subretinal fluid < 3 mm from margin
  14. 14. Group C Focal seeds  C1 Subretinal seeds < 3 mm from R.B  C2 Vitreous seeds < 3 mm from R.B  C3 Subretinal & vitreous seeds < 3 mm from R.B
  15. 15. Group D Diffuse seeds  D1 Subretinal seeds > 3 mm  D2 Vitreous seeds > 3mm  D3 Subretinal & vitreous seeds > 3 mm
  16. 16. Group E Extensive R.B  Occupying > 50% globe  Neovascular glaucoma  Opague media from haemorrhage in A.C & vitreous or subretinal space.  Invasion of postlaminar optic nerve, choroid (> 2 mm), sclera, orbit, A.C
  17. 17.  Leucocoria 56%  Strabismus 20%  Red painful eye 7%  Poor vision 5%  Asymptomatic 3%  Orbital cellulitis 3%  Unilateral mydriasis 2%  Heterochromia iridis 1%  Hyphema 1%
  18. 18.  Endophytic  Exophytic  Diffuse infiltrating tumor
  19. 19.  Tumor grows into vitreous cavity  yellow white mass  Progressively fills vitreous cavity & vitreous seeds occur  Retinal vessels not seen on tumor surface
  20. 20.  Tumor grows towards sclera  Solid R.D usually occurs  Retinal vessels seen on tumor surface
  21. 21.  Tumor diffusely involves retina causing placoid thickness of retina (not mass)  Seen in older children
  22. 22.  Grade 1 superficial involvement of optic nerve head only  Grade 2 Involvement upto or involving lamina cribrosa
  23. 23.  Grade 3 Involvement beyond lamina cribrosa  Grade 4 Involvement upto surgical margin
  24. 24.  History  Prenatal/natal/postnatal Maternal rubella ( cong. Cat.) Gestation period or delivery ( ROP ) Oxygen therapy ( ROP )  Family history 6% of RB pts have positive family history
  25. 25.  Physical examination Rule out tuberous sclerosis, cong. defects asso. with trisomy 13-15, rubella syndrome  Ocular examination Squint, leukocoria, heterochromia, proptosis, lymphadenopathy ( adv. cases ) pseudohypopyon, rubeosis iridis
  26. 26.  Detailed Anterior segment examination  I O P  Indirect Ophthalmoscopy with Scleral indentation  Fundus drawing denoting site & extent  Gross systemic examination
  27. 27.  Fully Dilated fundus examination Bilateral with 360 degree scleral depression Indirect ophthalmoscopy (diagnostic in 90% cases) Wide angle fundus camera ( Retcam)
  28. 28. rounded or irregular intraocular mass representing typical intralesional calcification
  29. 29.  delineates extraocular extension, can detect asso. Pinealoblastoma Cases with atypical manisfestations Diagnostic dilemma Extraocular &intracranial tumor extension is suspected
  30. 30. optic nerve invasion or intracranial extension
  31. 31.  Not required in routine work up.  Can be used to differentiate viable tumour from an avascular residue following radiotherapy or spontaneously regressed retinoblastoma.  Active lesion shows hypervascularity,dilated feeders and late staining
  32. 32.  AQUEOUS HUMOUR ENZYME ASSAY normal aqueous to plasma LDH >1.0 increased phosphoglucoisomerase levels increased neuron specific enolase levels
  33. 33.  Rarely done, invasive procedure  Approach through peripheral cornea, A/C, zonules, vitreous is recommended  Complication potential of needle track dissemination of tumor cells
  34. 34.  Useful in ruling out intracranial or distant spread as primary mode of spread of RB is hematogenous.  EXAMINATION OF SIBLINGS/PARENTS  To detect small lesions which may otherwise go undetected in siblings.  Parents may harbour regressed RB lesions.  Blood specimens of patient/parents/siblings should be taken for DNA analysis which could aid in genetic counselling.
  35. 35.  Congenital cataract 10% of all vision loss in children world wide prevalence of 1 to 6 cases per 10,000 live births cataract resulting from congenital rubella syndrome
  36. 36.  PHPV rare congenital developmental anomaly purely anterior (persistent tunica vasculosa lentis and persistent posterior fetal fibrovascular sheath of the lens) purely posterior (falciform retinal septum) and a combination of both
  37. 37.  Norrie disease Genetic disorder (inherited X link recessive) Features – shrinkage of globe wasting of the iris 30-50%have developmental delay/mental retardation Psychotic like features Behavioral abnormalities
  38. 38.  Coat’s disease Very rare, congenital non hereditary eye disorder Unilateral 6-8 years of age range ( 5 mnths to 71 yrs ) Blood leaks from abnormal vessels in back of the eye, leaving cholesterol deposits & damaging retina RD, Glaucoma, Atrophy, Cataracts secondary to Coat’s.
  39. 39.  ROP Oxygen toxicity, relative hypoxia Disorganized growth of retinal blood vessels ( scarring & RD )
  40. 40. Stage 1 is a faint demarcation line Stage 2 is an elevated ridge Stage 3 is extraretinal fibrovascular tissue Stage 4 is sub-total retinal detachment Stage 5 is total retinal detachment.
  41. 41.  Toxocariasis  Uveitis  Endophthalmitis  Retinal dysplasia  Retinoma
  42. 42. Special considerations for enucleation in R.B  Minimal manipulation  Avoid perforation of eye  Harvest long ( >15 mm) optic nerve stump  Inspect the enucleated eye for macroscopic extraocular extension & optic nerve involvement  Harvest fresh tissue for genetic studies  Place a primary implant  Avoid biointegrated implant if postoperative radiotherapy is necessary
  43. 43. Equatorial & Peripheral retinal tumors upto 4 mm in diameter & 2 mm in thickness. Triple freeze thaw cryotherapy at 4-6 week interval until complete tumor regression.
  44. 44.  Transient serous R.D  Retinal tear  Rhegmatogenous R.D
  45. 45.  Small post. tumors 4 mm basal diameter & 2 mm in thickness. Idea is too  Delimit tumor  Restrict blood supply to tumor by surrounding it with 2 rows of overlapping laser burns
  46. 46.  Transient serous R.D  Retinal vascular occlusion  Retinal hole  Retinal traction  Preretinal fibrosis  Large visual field defect ( tumor in juxtapapillary area)
  47. 47.  Pt on active chemoreduction protocol, restricts blood supply to tumor & reduces intraocular concentration of chemotherapeutic agent
  48. 48.  Day 1: vincristine + Etoposide + Carboplatin  Day 2: Etoposide Standard dose: (3 weekly, 6 cycles): Vincristine 1.5 mg/m2 (0.05 mg/kg for children < 36 mnths of age & maximum dose < 2 mg), Etoposide 150 mg/m2 (5 mg/kg for children < 36 mnths of age ), Carboplatin 560 mg/m2 (18.6 mg/kg for children < 36 mnths of age) High – dose (3 weekly, 6-12 cycles) : Vincristine 0.025 mg/kg, Etoposide 12 mg/kg, Carboplatin 28 mg/kg
  49. 49.  Focused heat generated by infrared radiation, applied to tissues at subphotocoagulation levels to induce tumor cell apoptosis.  Achieve slow & sustained ( 40 to 60 degree C) within tumor, sparing retinal vessels.  Transpupillary thermotherapy using infrared radiation from semiconductor diode laser delivered (1300 micron large spot indirect ophthalmoscope, operating microscope, transscleral route with diopexy probe).
  50. 50.  Tumor heated till it turns gray  Satisfactory control for small tumors(4 mm basal diam. & 2 mm thickness).  Complete tumor regression 85% (3-4 sessions)
  51. 51.  Focal iris atrophy  Focal paraxial lens opacity (minimised using 1300 micron indirect ophthalmoscope, duration 5 mins in single session)  Retinal traction  Serous R.D
  52. 52.  Placement of radioactive implant on sclera corresponding to base of tumor,transsclerally irradiate tumor.  Radioactive materials – Ruthenium 106 & Iodine 125  Tumors < 16mm basal diameter & < 8 mm thickness Primary or Secondary  Primary- chemotherapy is contraindicated, secondary treatment in eyes that fail to respond to chemoreduction & external beam radiotherapy or tumor recurrences.
  53. 53.  Tumor thickness measured by ultrasonography  Plaque design depending on basal tumor dimensions, its location & configuration e.g notched plaque used to protect optic nerve ( tumors peripapillary in location)  Dose – 4000 – 5000 cGy  Plaque sutured to sclera after tumor centration & left for duration of exposure (ranging 36 to 72 hrs)  90% tumor control
  54. 54.  Focal delivering of radiation, minimal damage to surrounding normal structures  Minimal periorbital tissue damage  Cosmetic abnormality absent, retarded bone growth in field of irradiation ( as in external beam radiotherapy )  Reduced risk of second malignant neoplasm  Shorter duration of treatment
  55. 55.  Radiation papillopathy  Radiation retinopathy
  56. 56.  Used less often, newer chemotherapy protocols  Indicated- primary chemotherapy & local therapy has failed or rarely chemotherapy is contraindicated.  Delivered using Cobalt 60 (gamma rays) or linear accelerator ( X-rays)  Linear accelerator with multi-beam technique, image guided radiotherapy & stereotactic radiotherapy, better treatment accuracy.
  57. 57.  Stunting of orbital growth  Dry eye  Cataract  Radiation retinopathy  Optic neuropathy  Second malignant neoplasms (hereditary form of retinoblastoma)  30% chance of another malignancy by 30 yrs  Risk of second malignant neoplasm greater in children under 12 mnths
  58. 58.  Buried  Non-buried
  59. 59.  Buried implants Better cosmosis & safety Materials used- plastic, silicone & hydroxyappatite ( currently recommended )
  60. 60.  Non- buried implants have problems of - migration extention infection
  61. 61.  Rare in developed countries  Common in developing countries  In Mexico, 18% of 500 pts presented with orbital RB  Taiwanese group, 36% (42 of 116) pts manifested orbital RB  In Nepal, incidence is higher 40% (19 of 43) with proptosis being most common manifestation of RB
  62. 62.  Primary orbital RB- clinical or radiologically detected orbital extension of intraocular RB at initial clinical presentation with or without proptosis or fungating mass. Silent proptosis without orbital & periocular inflammation in pt will manifest intraocular tumour,with inflammation indicates reactive sterile orbital cellulitis sec. to intraocular tumor necrosis.
  63. 63.  Secondary orbital RB- recurrence following uncomplicated enucleation for intraocular RB. Unexplained displacement, bulge or extrusion of previously well fitting conformer or prosthesis is an ominous finding sugg. of orbital recurrence
  64. 64.  Accidental orbital RB- Inadvertent perforation Fine-needle aspiration biopsy Intraocular surgery with unsuspected intraocular RB
  65. 65.  Overt orbital RB Unrecognized extrascleral or optic n. extension discovered during enucleation. Pale pink to cherry red episcleral nodule (juxtapapillary location or at site of vortex v.) Enlarged and inelastic optic n. with or without nodular optic n. sheath is an indicator of optic n. extension.
  66. 66.  Microscopic orbital RB Detection of full thickness scleral infiltration, extra scleral extension & invasion of optic n. on histopathologic evaluation on enucleated eye Tumor cells in choroidal & scleral emissaria & optic n. sheath indicates orbital extension.
  67. 67.  General physical examination- includes regional lymph nodes palpation  MRI or CT Scan of orbit & brain (axial & coronal orientation)  FNAC  Chest X-RAY  USG abdomen  Bone marrow biopsy  CSF cytology
  68. 68.  Combination therapy more effective Vincristine, Etoposide, Carboplatin high dose chemotherapy (3-6 cycles or even 12 cycles) followed by enucleation, extended enucleation or orbital exenteration

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