Retionblastoma

Grand RoundsGrand Rounds

Terry J. Alexandrou, MDTerry J. Alexandrou, MDDepartment of Ophthalmology and Visual Department of Ophthalmology and Visual

ScienceScienceThe University of ChicagoThe University of Chicago

1/4/20061/4/2006

HPI – Patient T.F.HPI – Patient T.F.

12/12/200512/12/2005

16 month old A.A. male presents with a 1 16 month old A.A. male presents with a 1 month history of “a left white pupil” and month history of “a left white pupil” and “left eye turning outwards”, according to “left eye turning outwards”, according to mom.mom.

PMHPMH

• NoneNone

• Full term – uncomplicated deliveryFull term – uncomplicated delivery

Meds and AllergiesMeds and Allergies

• Medications: NoneMedications: None

• Allergies: NKDAAllergies: NKDA

Family HistoryFamily History

NoneNone

Has a non-identical twin.Has a non-identical twin.

Mom complains of a “white pupil in the left Mom complains of a “white pupil in the left eye”eye”

Does the patient have a white pupil?Does the patient have a white pupil?

Always Listen to Mom!!!Always Listen to Mom!!!

EXAMEXAMVisual acuity:Visual acuity:

OD – Fix and FollowOD – Fix and FollowOS – Unable to fix or follow; Pt. becomes agitated with OS – Unable to fix or follow; Pt. becomes agitated with

occlusion of the right eyeocclusion of the right eyePupils: +LAPDPupils: +LAPD

Variable Exotropia – 30-40 prism dioptersVariable Exotropia – 30-40 prism diopters

Anterior Exam:Anterior Exam:- Cornea, AC, iris, lens normal OU- Cornea, AC, iris, lens normal OU

Fundus Exam:Fundus Exam:- Difficult, however able to see a moderately large - Difficult, however able to see a moderately large white mass in the left eye. Right eye appears normal.white mass in the left eye. Right eye appears normal.

• How would you pursue a diagnosis?How would you pursue a diagnosis?

Superior CutSuperior Cut

Inferior CutsInferior Cuts

Exam Under AnesthesiaExam Under Anesthesia

Left EyeLeft Eye

Left EyeLeft Eye

Left EyeLeft Eye

Differential?Differential?

RetinoblastomaRetinoblastoma

Coat’s DiseaseCoat’s Disease

Ocular toxocariasisOcular toxocariasis

Retinal Astrocytic HamartomaRetinal Astrocytic Hamartoma

Persistent Hyperplastic Primary Vitreous (PHPV)Persistent Hyperplastic Primary Vitreous (PHPV)

Retinopathy of PrematurityRetinopathy of Prematurity

RetinoblastomaRetinoblastoma

EpidemiologyEpidemiology

Most common intraocular malignancy in childrenMost common intraocular malignancy in children

1/15,000-1/20,000 live births1/15,000-1/20,000 live births

~300 new cases annually in the United States~300 new cases annually in the United States

No racial predilectionNo racial predilection

Occurs equally in males and femalesOccurs equally in males and females

Genetics – The Retinoblastoma GeneGenetics – The Retinoblastoma Gene

Tumor Suppressor GeneTumor Suppressor Gene

Chromosome 13 q 14Chromosome 13 q 14

Knudson’s “Two-Hit” Hypothesis – recessive at a Knudson’s “Two-Hit” Hypothesis – recessive at a cellular levelcellular level

Autosomal Dominant InheritanceAutosomal Dominant Inheritance

GeneticsGenetics

Non – Heritable Form (60%)Non – Heritable Form (60%)- - Average age at Diagnosis is 24 monthsAverage age at Diagnosis is 24 months

- Normal Life expectancy if cured of the eye tumor- Normal Life expectancy if cured of the eye tumor

- Unilateral- Unilateral

- Risk of additional cancers same as general population- Risk of additional cancers same as general population

Sporadic (93%) is not equivalent to Non-HeritableSporadic (93%) is not equivalent to Non-Heritable

GeneticsGenetics

Heritable Form (40%)Heritable Form (40%)- Family History in 7-10%- Family History in 7-10%

- New Germline Mutation in 30%- New Germline Mutation in 30%

- Average age at diagnosis is newborn to 12 months- Average age at diagnosis is newborn to 12 months

- Multiple, bilateral tumors in 85 %- Multiple, bilateral tumors in 85 %

- Predisposed to various cancers throughout life- Predisposed to various cancers throughout life

- midline intracranial tumor (pineal and suprasellar - midline intracranial tumor (pineal and suprasellar region)region)

-osteosarcomas and soft tissue sarcomas (teenage)-osteosarcomas and soft tissue sarcomas (teenage)

- melanomas and brain tumors (middle age)- melanomas and brain tumors (middle age)

- lung and bladder cancer (later life)- lung and bladder cancer (later life)

Clinical PresentationClinical Presentation

Leukocoria (54-62%)Leukocoria (54-62%)

Strabismus (18-22%)Strabismus (18-22%)

Red eyeRed eye

Excessive TearingExcessive Tearing

Corneal clouding (2/2 Corneal clouding (2/2 elevated IOP)elevated IOP)

HypopyonHypopyon

Discoloration of the iris (2/2 Discoloration of the iris (2/2 neovascularization)neovascularization)

ProptosisProptosis

Spontaneous Globe Spontaneous Globe perforationperforation

“Cat’s Eye” appearance

DiagnosisDiagnosis

Complete general historyComplete general history

Exam under anesthesiaExam under anesthesia

UltrasongraphyUltrasongraphy

CTCT

MRIMRI

Treatment OptionsTreatment Options

EnucleationEnucleation

Chemoreduction with Local tumor ablationChemoreduction with Local tumor ablation

CryotherapyCryotherapy

External-Beam Radiation TherapyExternal-Beam Radiation Therapy

BrachytherapyBrachytherapy

Treatment options in T.F.?Treatment options in T.F.?

International Classification for Intraocular International Classification for Intraocular RetinoblastomaRetinoblastoma

A) Group A (Very Low Risk) - Small discrete intraretinal tumors away A) Group A (Very Low Risk) - Small discrete intraretinal tumors away from the foveola and discfrom the foveola and disc

- All tumors are 3 mm or smaller in greatest dimension, confined to the retina - All tumors are 3 mm or smaller in greatest dimension, confined to the retina andand - All tumors are located further than 3 mm from the foveola and 1.5 mm from the optic disc - All tumors are located further than 3 mm from the foveola and 1.5 mm from the optic disc

B) Group B (Low Risk) - All remaining discrete retinal tumors without B) Group B (Low Risk) - All remaining discrete retinal tumors without seedingseeding - - All tumors confined to the retina not in group A All tumors confined to the retina not in group A

- Any tumor size and location with no vitreous or subretinal seeding - Any tumor size and location with no vitreous or subretinal seeding

C) C) Group C (Moderate Risk) - Discrete local disease with minimal focal Group C (Moderate Risk) - Discrete local disease with minimal focal subretinal or vitreous seedingsubretinal or vitreous seeding

--Tumor(s) must be discrete Tumor(s) must be discrete - Subretinal fluid, present or past, without gross seeding, involving up to one quadrant of retina - Subretinal fluid, present or past, without gross seeding, involving up to one quadrant of retina - Local subretinal seeding, present or past, less than 5 mm from the tumor - Local subretinal seeding, present or past, less than 5 mm from the tumor - Focal fine vitreous seeding close to discrete tumor - Focal fine vitreous seeding close to discrete tumor

D) Group D (High Risk) - Diffuse disease with significant vitreous D) Group D (High Risk) - Diffuse disease with significant vitreous and/or subretinal seedingand/or subretinal seeding

- Tumor(s) may be massive or diffuse - Tumor(s) may be massive or diffuse - Subretinal fluid, present or past up to total retinal detachment - Subretinal fluid, present or past up to total retinal detachment - Diffuse subretinal seeding, may include subretinal plaques or tumor nodules - Diffuse subretinal seeding, may include subretinal plaques or tumor nodules - Diffuse or massive vitreous disease may include "greasy" seeds or avascular tumor masses - Diffuse or massive vitreous disease may include "greasy" seeds or avascular tumor masses

E) Group E (Very High Risk) E) Group E (Very High Risk)

EnucleationEnucleation

Path – Gross SpecimenPath – Gross Specimen

Path - MicroPath - Micro

Not ready as of 1/3/06Not ready as of 1/3/06

Is Enucleation enough? Is Enucleation enough?

Are there any indications for adjuvant Are there any indications for adjuvant chemotherapy in this patient?chemotherapy in this patient?

What pathologic features are risk factors for What pathologic features are risk factors for metastatic disease in the future?metastatic disease in the future?

Pathologic features implicated in the pastPathologic features implicated in the past

Involvement of:Involvement of:

- Choroid - - Choroid - controversialcontroversial

- Optic nerve - Optic nerve –– posterior to lamina cribosaposterior to lamina cribosa

- residual tumor in optic nerve - residual tumor in optic nerve stump stump

- Sclera- Sclera

- Anterior Chamber- Anterior Chamber

CHILDREN’S ONCOLOGY GROUPCHILDREN’S ONCOLOGY GROUP

““A Study of Unilateral Retinoblastoma With A Study of Unilateral Retinoblastoma With andand

Without Histopathologic High-Risk FeaturesWithout Histopathologic High-Risk Features

and the Role of Adjuvant Chemotherapy”and the Role of Adjuvant Chemotherapy”

Study Chair: Murali Chintagumpala, MD (Baylor)Study Chair: Murali Chintagumpala, MD (Baylor)Study MembersStudy Members::

Joan O’ Brien, MD (Ophthalmology, UCSF)Joan O’ Brien, MD (Ophthalmology, UCSF)

Julie Stoner, Ph.D (Biostatistics, Nebraska)Julie Stoner, Ph.D (Biostatistics, Nebraska)

Katherine K. Matthay, MD (Hematology/Oncology, UCSF)Katherine K. Matthay, MD (Hematology/Oncology, UCSF)

Anna T. Meadows, MD (Oncology, Children’s Hospital of Anna T. Meadows, MD (Oncology, Children’s Hospital of Philadelphia)Philadelphia)

Ann M. Leahey, MD (Oncology, Children’s Hospital of Philadelphia)Ann M. Leahey, MD (Oncology, Children’s Hospital of Philadelphia)

Arupa Ganguly, Ph.D (Human Genetics, Penn)Arupa Ganguly, Ph.D (Human Genetics, Penn)

Robert Zimmerman, MD (Neuro-Radiology, Philadelphia)Robert Zimmerman, MD (Neuro-Radiology, Philadelphia)

Mary Herdy, CCRP (Michigan State University)Mary Herdy, CCRP (Michigan State University)

Marcus H. Pettigrew (Research Coordinator, COG)Marcus H. Pettigrew (Research Coordinator, COG)

Study PathologistsStudy Pathologists::

Daniel Albert, MD (Wisconsin)Daniel Albert, MD (Wisconsin)

Ralph Eagle, MD (Wills)Ralph Eagle, MD (Wills)

Patricia Chevez-Barrios, MD (The Methodist Hospital)Patricia Chevez-Barrios, MD (The Methodist Hospital)

GOALS AND OBJECTIVESGOALS AND OBJECTIVES

1)1) Prospectively determine the prevalence of high-risk Prospectively determine the prevalence of high-risk histopathologic features.histopathologic features.

2)2) Demonstrate that patients without certain high-risk Demonstrate that patients without certain high-risk features can be successfully treated with enucleation features can be successfully treated with enucleation alone.alone.

3)3) Estimate the event-free survival and overall survival in Estimate the event-free survival and overall survival in patients with certain high-risk features who are treated patients with certain high-risk features who are treated with adjuvant chemotherapy.with adjuvant chemotherapy.

4)4) Estimate the incidence of toxicities associated with the Estimate the incidence of toxicities associated with the proposed adjuvant chemotherapy.proposed adjuvant chemotherapy.

Eligibility CriteriaEligibility Criteria• Age: 0 to 6 yearsAge: 0 to 6 years

• Diagnosis: All newly diagnosed children with Unilateral Diagnosis: All newly diagnosed children with Unilateral Retinoblastoma who undergo enucleation as initial therapyRetinoblastoma who undergo enucleation as initial therapy

• Performance Level: Lansky score > 50Performance Level: Lansky score > 50

• Prior Therapy: No prior therapy other than enucleationPrior Therapy: No prior therapy other than enucleation

• Baseline MRI of the brainBaseline MRI of the brain

• Organ Function Requirements: For patients with high-risk features Organ Function Requirements: For patients with high-risk features who are to receive chemotherapywho are to receive chemotherapy

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 TherapyMay enter other protocols

Follow-up

High-Risk Histopathologic FeaturesHigh-Risk Histopathologic Features

a)a) Posterior Uveal Invasion (includes choroidal invasion)Posterior Uveal Invasion (includes choroidal invasion)

b)b) Any degree of concomitant choroid and optic n. involvementAny degree of concomitant choroid and optic n. involvement

c)c) Tumor involving the optic n. posterior to the lamina cribosa as an Tumor involving the optic n. posterior to the lamina cribosa as an independent findingindependent finding

d)d) Scleral invasionScleral invasion

e)e) Anterior Chamber seedingAnterior Chamber seeding

f)f) Ciliary body infiltrationCiliary body infiltration

g)g) Iris infiltrationIris infiltration

High-Risk Histopathologic Features for High-Risk Histopathologic Features for which Adjuvant Therapy is Indicatedwhich Adjuvant Therapy is Indicated

a)a) Massive choroid replacement (Posterior Uveal invasion grades Massive choroid replacement (Posterior Uveal invasion grades IIC and IID)IIC and IID)

b)b) Any posterior uveal involvement with any optic nerve Any posterior uveal involvement with any optic nerve involvementinvolvement

c)c) Optic nerve involvement posterior to the lamina cribosaOptic nerve involvement posterior to the lamina cribosa

Posterior Uveal InvolvementPosterior Uveal InvolvementI: Posterior uveal invasion absentI: Posterior uveal invasion absentII: Posterior uveal invasion presentII: Posterior uveal invasion present

IIA: largest dimension of tumor on slide < 1 mmIIA: largest dimension of tumor on slide < 1 mmIIB: largest dimension between 1-3 mmIIB: largest dimension between 1-3 mmIIC: largest dimension > 3 mmIIC: largest dimension > 3 mmIID: posterior uveal tumor noted grosslyIID: posterior uveal tumor noted grossly

Treatment PlanTreatment Plan

• Treatment to start within 4 weeks of enucleationTreatment to start within 4 weeks of enucleation

• Consists of 6 cycles of Carboplantin, Etoposide and Consists of 6 cycles of Carboplantin, Etoposide and Vincristine given every 4 weeksVincristine given every 4 weeks

• Long term follow-up of patientsLong term follow-up of patients

Financial considerationsFinancial considerations

12/12/05 12/12/05 - New Ophth Patient $187.00- New Ophth Patient $187.00

12/13/0512/13/05- CT under anesthesia $3,112- CT under anesthesia $3,112

12/15/0512/15/05- Exam under anesthesia $9,075- Exam under anesthesia $9,075

12/21/0512/21/05- Enucleation $16,259- Enucleation $16,259

No payments received yet.No payments received yet.

Practice based learningPractice based learning

1) Complete exam should be performed on 1) Complete exam should be performed on parents and siblings of retinoblastoma parents and siblings of retinoblastoma patientspatients

2) Always listen to the parents – we have the 2) Always listen to the parents – we have the patients in our office for 30 minutespatients in our office for 30 minutes

Systems based LearningSystems based Learning

1) Coordinate efforts between different 1) Coordinate efforts between different specialties specialties