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Grand Rounds Terry J. Alexandrou, MD Department of Ophthalmology and Visual Science The University of Chicago 1/4/2006
HPI – Patient T.F. <ul><li>12/12/2005 </li></ul><ul><li>16 month old A.A. male presents with a 1 month history of “a left ...
PMH <ul><li>None </li></ul><ul><li>Full term – uncomplicated delivery </li></ul>
Meds and Allergies <ul><li>Medications:  None </li></ul><ul><li>Allergies: NKDA </li></ul>
Family History <ul><li>None </li></ul><ul><li>Has a non-identical twin. </li></ul>
Mom complains of a “white pupil in the left eye” <ul><li>Does the patient have a white pupil? </li></ul>
Always Listen to Mom!!!
EXAM <ul><li>Visual acuity: </li></ul><ul><li>OD – Fix and Follow </li></ul><ul><li>OS – Unable to fix or follow; Pt. beco...
<ul><li>How would you pursue a diagnosis? </li></ul>
Superior Cut
Inferior Cuts
<ul><li>Exam Under Anesthesia </li></ul>
Left Eye
Left Eye
Left Eye
<ul><li>Differential? </li></ul>
<ul><li>Retinoblastoma </li></ul><ul><li>Coat’s Disease </li></ul><ul><li>Ocular toxocariasis </li></ul><ul><li>Retinal As...
Retinoblastoma <ul><li>Epidemiology </li></ul><ul><li>Most common intraocular malignancy in children </li></ul><ul><li>1/1...
<ul><li>Genetics – The Retinoblastoma Gene </li></ul><ul><li>Tumor Suppressor Gene </li></ul><ul><li>Chromosome 13 q 14 </...
<ul><li>Genetics </li></ul><ul><li>Non – Heritable Form (60%) </li></ul><ul><li>-  Average age at Diagnosis is 24 months <...
<ul><li>Genetics </li></ul><ul><li>Heritable Form (40%) </li></ul><ul><li>- Family History in 7-10% </li></ul><ul><li>- Ne...
<ul><li>Clinical Presentation </li></ul><ul><li>Leukocoria (54-62%) </li></ul><ul><li>Strabismus (18-22%) </li></ul><ul><l...
<ul><li>Diagnosis </li></ul><ul><li>Complete general history </li></ul><ul><li>Exam under anesthesia </li></ul><ul><li>Ult...
<ul><li>Treatment Options </li></ul><ul><li>Enucleation </li></ul><ul><li>Chemoreduction with Local tumor ablation </li></...
<ul><li>International Classification for Intraocular Retinoblastoma   </li></ul><ul><li>A)  Group A (Very Low Risk) - Smal...
Enucleation
Path – Gross Specimen
Path - Micro <ul><li>Not ready as of 1/3/06 </li></ul>
<ul><li>Is Enucleation enough?  </li></ul><ul><li>Are there any indications for adjuvant chemotherapy in this patient? </l...
Pathologic features implicated in the past <ul><li>Involvement of: </li></ul><ul><li>- Choroid -  controversial </li></ul>...
CHILDREN’S ONCOLOGY GROUP <ul><li>“ A Study of Unilateral Retinoblastoma With and </li></ul><ul><li>Without Histopathologi...
<ul><li>Study Chair: Murali Chintagumpala, MD (Baylor) </li></ul><ul><li>Study Members : </li></ul><ul><li>Joan O’ Brien, ...
GOALS AND OBJECTIVES <ul><li>Prospectively determine the prevalence of high-risk histopathologic features. </li></ul><ul><...
Eligibility Criteria <ul><li>Age: 0 to 6 years </li></ul><ul><li>Diagnosis: All newly diagnosed children with Unilateral R...
Unilateral Disease High-Risk Histopathologic Features for which Adjuvant Therapy is Indicated No High-Risk Histopathologic...
High-Risk Histopathologic Features <ul><li>Posterior Uveal Invasion (includes choroidal invasion) </li></ul><ul><li>Any de...
High-Risk Histopathologic Features for which Adjuvant Therapy is Indicated <ul><li>Massive choroid replacement (Posterior ...
Treatment Plan <ul><li>Treatment to start within 4 weeks of enucleation </li></ul><ul><li>Consists of 6 cycles of Carbopla...
<ul><li>Financial considerations </li></ul><ul><li>12/12/05  </li></ul><ul><li>- New Ophth Patient  $187.00 </li></ul><ul>...
<ul><li>Practice based learning </li></ul><ul><li>1) Complete exam should be performed on parents and siblings of retinobl...
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Retinoblastoma

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  1. 1. Grand Rounds Terry J. Alexandrou, MD Department of Ophthalmology and Visual Science The University of Chicago 1/4/2006
  2. 2. HPI – Patient T.F. <ul><li>12/12/2005 </li></ul><ul><li>16 month old A.A. male presents with a 1 month history of “a left white pupil” and “left eye turning outwards”, according to mom. </li></ul>
  3. 3. PMH <ul><li>None </li></ul><ul><li>Full term – uncomplicated delivery </li></ul>
  4. 4. Meds and Allergies <ul><li>Medications: None </li></ul><ul><li>Allergies: NKDA </li></ul>
  5. 5. Family History <ul><li>None </li></ul><ul><li>Has a non-identical twin. </li></ul>
  6. 6. Mom complains of a “white pupil in the left eye” <ul><li>Does the patient have a white pupil? </li></ul>
  7. 7. Always Listen to Mom!!!
  8. 8. EXAM <ul><li>Visual acuity: </li></ul><ul><li>OD – Fix and Follow </li></ul><ul><li>OS – Unable to fix or follow; Pt. becomes agitated with </li></ul><ul><li>occlusion of the right eye </li></ul><ul><li>Pupils: +LAPD </li></ul><ul><li>Variable Exotropia – 30-40 prism diopters </li></ul><ul><li>Anterior Exam: </li></ul><ul><li>- Cornea, AC, iris, lens normal OU </li></ul><ul><li>Fundus Exam: </li></ul><ul><li>- Difficult, however able to see a moderately large white mass in the left eye. Right eye appears normal. </li></ul>
  9. 9. <ul><li>How would you pursue a diagnosis? </li></ul>
  10. 10. Superior Cut
  11. 11. Inferior Cuts
  12. 12. <ul><li>Exam Under Anesthesia </li></ul>
  13. 13. Left Eye
  14. 14. Left Eye
  15. 15. Left Eye
  16. 16. <ul><li>Differential? </li></ul>
  17. 17. <ul><li>Retinoblastoma </li></ul><ul><li>Coat’s Disease </li></ul><ul><li>Ocular toxocariasis </li></ul><ul><li>Retinal Astrocytic Hamartoma </li></ul><ul><li>Persistent Hyperplastic Primary Vitreous (PHPV) </li></ul><ul><li>Retinopathy of Prematurity </li></ul>
  18. 18. Retinoblastoma <ul><li>Epidemiology </li></ul><ul><li>Most common intraocular malignancy in children </li></ul><ul><li>1/15,000-1/20,000 live births </li></ul><ul><li>~300 new cases annually in the United States </li></ul><ul><li>No racial predilection </li></ul><ul><li>Occurs equally in males and females </li></ul>
  19. 19. <ul><li>Genetics – The Retinoblastoma Gene </li></ul><ul><li>Tumor Suppressor Gene </li></ul><ul><li>Chromosome 13 q 14 </li></ul><ul><li>Knudson’s “Two-Hit” Hypothesis – recessive at a cellular level </li></ul><ul><li>Autosomal Dominant Inheritance </li></ul>
  20. 20. <ul><li>Genetics </li></ul><ul><li>Non – Heritable Form (60%) </li></ul><ul><li>- Average age at Diagnosis is 24 months </li></ul><ul><li>- Normal Life expectancy if cured of the eye tumor </li></ul><ul><li>- Unilateral </li></ul><ul><li>- Risk of additional cancers same as general population </li></ul><ul><li>Sporadic (93%) is not equivalent to Non-Heritable </li></ul>
  21. 21. <ul><li>Genetics </li></ul><ul><li>Heritable Form (40%) </li></ul><ul><li>- Family History in 7-10% </li></ul><ul><li>- New Germline Mutation in 30% </li></ul><ul><li>- Average age at diagnosis is newborn to 12 months </li></ul><ul><li>- Multiple, bilateral tumors in 85 % </li></ul><ul><li>- Predisposed to various cancers throughout life </li></ul><ul><li>- midline intracranial tumor (pineal and suprasellar region) </li></ul><ul><li>-osteosarcomas and soft tissue sarcomas (teenage) </li></ul><ul><li>- melanomas and brain tumors (middle age) </li></ul><ul><li>- lung and bladder cancer (later life) </li></ul>
  22. 22. <ul><li>Clinical Presentation </li></ul><ul><li>Leukocoria (54-62%) </li></ul><ul><li>Strabismus (18-22%) </li></ul><ul><li>Red eye </li></ul><ul><li>Excessive Tearing </li></ul><ul><li>Corneal clouding (2/2 elevated IOP) </li></ul><ul><li>Hypopyon </li></ul><ul><li>Discoloration of the iris (2/2 neovascularization) </li></ul><ul><li>Proptosis </li></ul><ul><li>Spontaneous Globe perforation </li></ul>“ Cat’s Eye” appearance
  23. 23. <ul><li>Diagnosis </li></ul><ul><li>Complete general history </li></ul><ul><li>Exam under anesthesia </li></ul><ul><li>Ultrasongraphy </li></ul><ul><li>CT </li></ul><ul><li>MRI </li></ul>
  24. 24. <ul><li>Treatment Options </li></ul><ul><li>Enucleation </li></ul><ul><li>Chemoreduction with Local tumor ablation </li></ul><ul><li>Cryotherapy </li></ul><ul><li>External-Beam Radiation Therapy </li></ul><ul><li>Brachytherapy </li></ul><ul><li>Treatment options in T.F.? </li></ul>
  25. 25. <ul><li>International Classification for Intraocular Retinoblastoma </li></ul><ul><li>A) Group A (Very Low Risk) - Small discrete intraretinal tumors away from the foveola and disc </li></ul><ul><li>- All tumors are 3 mm or smaller in greatest dimension, confined to the retina and </li></ul><ul><li>- All tumors are located further than 3 mm from the foveola and 1.5 mm from the optic disc </li></ul><ul><li>B) Group B (Low Risk) - All remaining discrete retinal tumors without seeding </li></ul><ul><li> - All tumors confined to the retina not in group A </li></ul><ul><li>- Any tumor size and location with no vitreous or subretinal seeding </li></ul><ul><li>C) Group C (Moderate Risk) - Discrete local disease with minimal focal subretinal or vitreous seeding </li></ul><ul><li>- Tumor(s) must be discrete </li></ul><ul><li>- Subretinal fluid, present or past, without gross seeding, involving up to one quadrant of retina </li></ul><ul><li>- Local subretinal seeding, present or past, less than 5 mm from the tumor </li></ul><ul><li>- Focal fine vitreous seeding close to discrete tumor </li></ul><ul><li>D) Group D (High Risk) - Diffuse disease with significant vitreous and/or subretinal seeding </li></ul><ul><li>- Tumor(s) may be massive or diffuse </li></ul><ul><li>- Subretinal fluid, present or past up to total retinal detachment </li></ul><ul><li>- Diffuse subretinal seeding, may include subretinal plaques or tumor nodules </li></ul><ul><li>- Diffuse or massive vitreous disease may include &quot;greasy&quot; seeds or avascular tumor masses </li></ul><ul><li>E) Group E (Very High Risk) </li></ul>
  26. 26. Enucleation
  27. 27. Path – Gross Specimen
  28. 28. Path - Micro <ul><li>Not ready as of 1/3/06 </li></ul>
  29. 29. <ul><li>Is Enucleation enough? </li></ul><ul><li>Are there any indications for adjuvant chemotherapy in this patient? </li></ul><ul><li>What pathologic features are risk factors for metastatic disease in the future? </li></ul>
  30. 30. Pathologic features implicated in the past <ul><li>Involvement of: </li></ul><ul><li>- Choroid - controversial </li></ul><ul><li>- Optic nerve – posterior to lamina cribosa </li></ul><ul><li> - residual tumor in optic nerve stump </li></ul><ul><li>- Sclera </li></ul><ul><li>- Anterior Chamber </li></ul>
  31. 31. CHILDREN’S ONCOLOGY GROUP <ul><li>“ A Study of Unilateral Retinoblastoma With and </li></ul><ul><li>Without Histopathologic High-Risk Features </li></ul><ul><li>and the Role of Adjuvant Chemotherapy” </li></ul>
  32. 32. <ul><li>Study Chair: Murali Chintagumpala, MD (Baylor) </li></ul><ul><li>Study Members : </li></ul><ul><li>Joan O’ Brien, MD (Ophthalmology, UCSF) </li></ul><ul><li>Julie Stoner, Ph.D (Biostatistics, Nebraska) </li></ul><ul><li>Katherine K. Matthay, MD (Hematology/Oncology, UCSF) </li></ul><ul><li>Anna T. Meadows, MD (Oncology, Children’s Hospital of Philadelphia) </li></ul><ul><li>Ann M. Leahey, MD (Oncology, Children’s Hospital of Philadelphia) </li></ul><ul><li>Arupa Ganguly, Ph.D (Human Genetics, Penn) </li></ul><ul><li>Robert Zimmerman, MD (Neuro-Radiology, Philadelphia) </li></ul><ul><li>Mary Herdy, CCRP (Michigan State University) </li></ul><ul><li>Marcus H. Pettigrew (Research Coordinator, COG) </li></ul><ul><li>Study Pathologists : </li></ul><ul><li>Daniel Albert, MD (Wisconsin) </li></ul><ul><li>Ralph Eagle, MD (Wills) </li></ul><ul><li>Patricia Chevez-Barrios, MD (The Methodist Hospital) </li></ul>
  33. 33. GOALS AND OBJECTIVES <ul><li>Prospectively determine the prevalence of high-risk histopathologic features. </li></ul><ul><li>Demonstrate that patients without certain high-risk features can be successfully treated with enucleation alone. </li></ul><ul><li>Estimate the event-free survival and overall survival in patients with certain high-risk features who are treated with adjuvant chemotherapy. </li></ul><ul><li>Estimate the incidence of toxicities associated with the proposed adjuvant chemotherapy. </li></ul>
  34. 34. Eligibility Criteria <ul><li>Age: 0 to 6 years </li></ul><ul><li>Diagnosis: All newly diagnosed children with Unilateral Retinoblastoma who undergo enucleation as initial therapy </li></ul><ul><li>Performance Level: Lansky score > 50 </li></ul><ul><li>Prior Therapy: No prior therapy other than enucleation </li></ul><ul><li>Baseline MRI of the brain </li></ul><ul><li>Organ Function Requirements: For patients with high-risk features who are to receive chemotherapy </li></ul>
  35. 35. Unilateral Disease High-Risk Histopathologic Features for which Adjuvant Therapy is Indicated No High-Risk Histopathologic Features for which Adjuvant Therapy is indicated No Metastatic Disease 6 cycles of Chemotherapy Observation Metastatic Disease No Metastatic Disease Follow-up Off Protocol Therapy May enter other protocols Follow-up
  36. 36. High-Risk Histopathologic Features <ul><li>Posterior Uveal Invasion (includes choroidal invasion) </li></ul><ul><li>Any degree of concomitant choroid and optic n. involvement </li></ul><ul><li>Tumor involving the optic n. posterior to the lamina cribosa as an independent finding </li></ul><ul><li>Scleral invasion </li></ul><ul><li>Anterior Chamber seeding </li></ul><ul><li>Ciliary body infiltration </li></ul><ul><li>Iris infiltration </li></ul>
  37. 37. High-Risk Histopathologic Features for which Adjuvant Therapy is Indicated <ul><li>Massive choroid replacement (Posterior Uveal invasion grades IIC and IID) </li></ul><ul><li>Any posterior uveal involvement with any optic nerve involvement </li></ul><ul><li>Optic nerve involvement posterior to the lamina cribosa </li></ul><ul><li>Posterior Uveal Involvement </li></ul><ul><li>I: Posterior uveal invasion absent </li></ul><ul><li>II: Posterior uveal invasion present </li></ul><ul><li>IIA: largest dimension of tumor on slide < 1 mm </li></ul><ul><li>IIB: largest dimension between 1-3 mm </li></ul><ul><li>IIC: largest dimension > 3 mm </li></ul><ul><li>IID: posterior uveal tumor noted grossly </li></ul>
  38. 38. Treatment Plan <ul><li>Treatment to start within 4 weeks of enucleation </li></ul><ul><li>Consists of 6 cycles of Carboplantin, Etoposide and Vincristine given every 4 weeks </li></ul><ul><li>Long term follow-up of patients </li></ul>
  39. 39. <ul><li>Financial considerations </li></ul><ul><li>12/12/05 </li></ul><ul><li>- New Ophth Patient $187.00 </li></ul><ul><li>12/13/05 </li></ul><ul><li>- CT under anesthesia $3,112 </li></ul><ul><li>12/15/05 </li></ul><ul><li>- Exam under anesthesia $9,075 </li></ul><ul><li>12/21/05 </li></ul><ul><li>- Enucleation $16,259 </li></ul><ul><li>No payments received yet. </li></ul>
  40. 40. <ul><li>Practice based learning </li></ul><ul><li>1) Complete exam should be performed on parents and siblings of retinoblastoma patients </li></ul><ul><li>2) Always listen to the parents – we have the patients in our office for 30 minutes </li></ul><ul><li>Systems based Learning </li></ul><ul><li>1) Coordinate efforts between different specialties </li></ul>

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