RETINOBLASTOMA

Dr. Pavan Naik

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.

INTRODUCTIONPrimary 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 childhoodUnifocal/multifocal. Unilateral (70%) or bilateral (30%).Sporadic (94%) or familial (6%). Non hereditary (50-60%) or hereditary (40-

50%).

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.

Frequency is shown as a function of age at diagnosis in subgroups of unilateral versus bilateral disease.

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).

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.

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)

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).

For retinoblastoma to occur both the allels

have to be deleted If only one allel is deleted it is called 13q

deletion syndrome

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…

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

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.

CLINICAL MANIFESTATIONSMANIFESTATION PERCENTAGELEUCOCORIA 56%STRABISMUS 20%RED PAINFUL EYE 7%POOR VISION 5%ASYMPTOMATIC 3%ORBITAL CELLULITIS 3%UNILATERAL MYDRIASIS 2%HETEROCHROMIA IRIDID 1%HYPHEMA 1%

CLINICAL MANIFESTATIONS

9. Proptosis of eye

LEUCOCORIA

PATTERNS OF GROWTH

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

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

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

ROUTES OF SPREAD

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

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

RETINOMA-spontaneously arrested retinoblastomaLimited vascularityGreyish-whiteSpeckledSurrounding chorio-retinal atrophyRPE hypertrophy

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

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

FleurettesTumor cells with pear shaped eosinophilic processes projecting through a fenestrated membrane

DIFFERENTIAL DIAGNOSISDifferential Diagnosis of Leukokoria Coats’ disease Persistent hyperplastic primary vitreous Ocular toxocariasis Cicatricial retinopathy of prematurity Familial exudative vitreoretinopathy Incontinentia pigmenti retinopathy Norrie’s diseaseDifferential Diagnosis of Vitreous Seeds Pars planitis (intermediate uveitis) Microbial endophthalmitis or retinitis Leukemic infiltrationDifferential Diagnosis of Discrete Retinal Tumors Astrocytoma of retina

Medulloepithelioma Retinal capillary hemangioma Focal patches of myelinated retinal nerve fiber

LEUCOCORIA

TO BE CONTINUED IN NEXT CLASS

STAGINGDAIGNOSISTREATMENT

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

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

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

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

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

FFA Not usually performed Rapid filling of feeder vessel-intraretinal

vasculature-draining of efferent vein Intralesional capillaries-leak fluoroscein

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

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.

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[∗]

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

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

STAGING

PROGNOSTIC FACTORS

MANAGEMENT Primary goal-save life Salvage of the organ and function-secondary and

tertiary Multidisciplinary approach Individualised –depends on 1. Age2. Laterality3. Location4. Staging5. Systemic condition6. Overall progression7. Cost effectiveness

CURRENT SUGGESTED PROTOCOL A Intraocular tumor- international classification

group-A-C U/L or B/L1. Focal-cryotherapy/transpupillary thermotherapy

tumors<3mm in visually non crucial areas2. 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

B. Intraocular tumor, Group D U/L or B/L1. High dose chemotherapy/aggressive focal

therapy2. Periocular carboplatin –vitreous seeds3. Primary enucleation-U/L- esp with no visual

prognosis

C. Group E U/L or B/L 1. Primary enucleation2. Evaluate histopathology for high risk factors

D. High risk factors on HPE- Stage 2 1. Baseline systemic evaluation for metastasis2. Standard 6 cycle adjuvant therapy3. High dose adjuvant chemotherapy + orbital

EBRT- with scleral infiltration, extraocular extension, optic nerve extension

E. Extraocular tumor-Stage 3A 1. Baseline systemic evaluation for metastases2. High dose chemotherapy-3-6 cycles followed

by enucleation/extended enucleation, EBRT, high dose chemo 12 cycles

F. Regional LN metastasis Stage 3B1. Baseline evaluation for systemic metastasis2. Neck dissection, high dose chemotherapy for

6 cycles, followed by EBRT and high dose chemotherapy-12 cycles

G. Hematogenous /CNS metastasis-Stage 41. Palliative therapy 2. High dose chemotherapy –BM rescue3. High dose chemotherapy- intrathecal

chemotherapy for CNS metastases

TREATMENT TREATMENT OPTIONS FOR INTRAOCULAR

RETINOBLASTOMA  Intravenous chemotherapy

Enucleation Radiation therapy • External beam radiation therapy • Plaque radiotherapy Laser therapy • Photocoagulation • Transpupillary thermotherapy (TTT)

CryotherapyObservation (for spontaneously arrested

retinoblastoma, retinoma)

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 subretinal seeds) regress substantially within the first two cycles

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.

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

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.

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..

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

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

Orbital implants

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

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

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

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.

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

<16mm basal diameter, < 8 mm thickness Notched plaque to protect optic nerve To apex-4000-5000cGy Sutured to sclera, left in situ-36-72hrs

A.PRETREATMENT MACULAR RETINOBLASTOMA

B.POST PLAQUE RT-REGESSED

Ruthenium plaque sutured to sclera

LASER THERAPY

1. PHOTOCOAGULATION 2. TRANS-PUPILLARY THERMOTHERAPY

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.

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

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

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.

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

SIDE EFFECTS Transient RD Retinal tear

COURSE & OUTCOME

REFERENCES1. Yanoff Textbook of Ophthalmology 3 rd

edition-887-8942. Retinoblastoma AIOS series No 253. Indian journal of ophthalmology-April 2012

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