RetinoblastomaRetinoblastoma

Othman Al-Abbadi, M.D

HISTORY

• Peter Pawius of Amsterdam provided the first description of a tumor resembling retinoblastoma in 1597. The tumor was described as filled with a "substance similar to brain tissue mixed with thick blood and like crushed stone."• In 1805… termed as fungal hematode.• In 1809, Wardop concluded its arousal from the

retina and suggested enucleation as primary mode of management.• In 1926… it was termed as retinoblastoma by the

AAO.• In 1970, Tso and colleagues established that the

tumor arises from photoreceptor precursors.

• Retinoblastoma tumor cells grown in culture have been shown to express a red and a green photopigment gene, as well as cone cell alpha subunits of transducin. These findings further support the concept that retinoblastoma may be a neoplasm of cone cell lineage.

• The so-called retinoblastoma gene is deceptively named, as it does not actively cause retinoblastoma. The normal gene suppresses the development of retinoblastoma.

• Retinoblastoma develops when both homologous loci of the suppressor gene become nonfunctional either by a deletion error or by mutation. Although 1 normal gene is sufficient to suppress the development of retinoblastoma, the presence of 1 normal gene and 1 abnormal gene is apparently an unstable situation that may lead to mutation in the normal gene and the loss of tumor suppression, thus allowing retinoblastoma to develop.

INTRODUCTION

• Retinoblastoma is the most common primary intraocular malignant tumor of childhood

• Results from mutation of the RB1 gene located at the long arm of chromosome 13 (13q14)

EPIDEMIOLOGY

• Most common primary intraocular malignancy of childhood• 3% of all childhood cancers• Third most common intraocular malignancy after

Uveal melanoma & Metastasis• Incidence 1:18.000• 90% present before 3 years of age• No racial, gender nor side predilection• 60% unilateral… diagnosed at 24 months• 40% bilateral… diagnosed at 14 months

GENETICS • Retinoblastoma is caused by a mutation in the RB1 tumor

suppressor gene located on the long arm of chromosome 13 at locus 14 (13q14).

• Both copies of the RB1 gene must be mutated in order for a tumor to form.

• If a patient has bilateral retinoblastoma, there is approximately a 98% chance that it represents a germline mutation. Only about 5% of retinoblastoma patients have a family history of retinoblastoma. The children of a retinoblastoma survivor who has the hereditary form of retinoblastoma have a 45% chance of being affected (50% chance of inheriting and 90% chance of penetrance). In these cases, the child inherits an abnormal gene from the affected parent. This abnormal gene coupled with somatic mutations in the remaining normal RB1 allele leads to the development of multiple tumors in 1 or both eyes.

• Inherited as autosomal Dominant (genetic level)

• Acts as autosomal Recessive (cellular level)• Penetrance

• Heritable• 40%• Transmissible to offspring• One pair is mutated in all cells of the body• Two-hit hypothesis for malignant transformation• Risk for bilateral & multifocal• Risk for non-ocular tumors; Pinealoblastoma,

Osteosarcoma, soft tissue sarcoma, Melanoma & small cell lung cancer

• Risk of second malignancy is 6%• Risk increases 5-folds if exposed to radiation

• Non-heritable (Somatic)• 60%• Solitary & unilateral• No increased risk for non-ocular cancers• Risk in siblings is 1%

SCREENING

• Detection of mutations in RB1 has approached 95% in recent years.• Siblings at risk of retinoblastoma should be

screened by prenatal ultrasonography, by ophthalmoscopy soon after birth and then regularly until the age of 4 or 5 years. • Early diagnosis correlates with a higher chance of

1preserving vision, 2salvaging the eye and 3preserving life. • If a child has heritable retinoblastoma, the risk to

siblings is 2% if the parents are healthy, and 40% if a parent is affected.

PRESENTATION

TYPES OF GROWTH

• Intraretinal• Homogeneous, dome-shaped white lesion often with

white flecks of calcification• Endophytic• Projects into the vitreous as a white mass that may ‘seed’

into the vitreous• Exophytic • Multilobular subretinal white masses causing overlying

retinal detachment

INTRARETINAL

ENDOPHYTIC • Tumor grows into vitreous cavity

• yellow white mass

• Progressively fills vitreous cavity & vitreous

seeds occur

• Retinal vessels not seen on tumor surface

VITREOUS SEEDING

PSEUDOHYPOPION

VITREOUS SEEDING

EXOPHYTIC

• Tumor grows towards sclera• R.D usually occurs• Retinal vessels seen on tumor surface

GRADES OF OPTIC NERVE INVOLVEMENT

• Grade 1superficial involvement of optic nerve head only

• Grade 2 Involvement upto or involving lamina

cribrosa

• Grade 3Involvement beyond lamina cribrosa

• Grade 4Involvement upto surgical margin

EXTENSION

• Optic nerve • Most common• To the subarachnoid space

• Orbit … through sclera• Conjunctival lymphatics… through TM• Metz• Skull & distant bones• Brain & spinal cord• Lymph nodes• Abdominal viscera

INVESTIGATIONS

RED REFLEX TESTING

EUA

• General examination for congenital abnormalities of the face and hands• Corneal diameter• Tonometry• AC examination• Fundus exam with scleral indentation • Cycloplegic refraction

RB ON SCLERAL INDENTATION

ULTRASOUND• Assess tumour size• Calcification

3D U S

WIDE-FIELD PHOTOGRAPHY

• Surveying and documentation• advantages in the management of retinoblastoma

C T SCAN

• Detects calcification• Delineates extraocular extension

M R I

• Does not detect calcification• Optic nerve evaluation• Detection of extraocular extension• Preferred over CT

M R I

FINE NEEDLE ASPIRATION BIOPSY

• Rarely done, invasive procedure

• Approach through peripheral cornea, A/C, zonules, vitreous is recommended

WHY NO TO FNA

• Taking a biopsy specimen from a tumor in the eye can’t be done easily without harming the eye and risking spreading cancer cells outside the eye. • Retinoblastoma can usually be diagnosed

accurately without a biopsy

SYSTEMIC ASSESSMENT

• Includes physical examination and MRI scans of the orbit and skull as a minimum in high-risk cases.

• If these indicate the presence of metastatic disease then bone scans, bone marrow aspiration and lumbar puncture are also performed.

GENETIC STUDIES

• 1Tumour tissue and 2blood samples from the patient and relatives

CLASSIFICATION

REESE-ELLSWORTH CLASSIFICATION

INTERNATIONAL CLASSIFICATION

TREATMENT

• The first and foremost important to understand that it is a malignancy.

• When the disease is contained within the eye, survival rates exceed 95% in the Western world. However, with extraocular spread, survival rates decrease to under 50%.

• Therefore, when a treatment strategy is being decided, the first goal must be 1preservation of life, then 2preservation of the eye, and, finally, 3preservation of vision.

• The modern management of intraocular retinoblastoma currently incorporates a combination of different treatment modalities

CHEMOTHERAPY

• The mainstay of treatment in most cases• Intravenous• Intravitreal• Selective ophthalmic artery infusion• Sub-Tenon

• Intravenous carboplatin, etoposide and vincristine (CEV) are given in 3-6 cycles every 3-4 weeks according to the grade of retinoblastoma • Chemoreduction may be followed by focal

treatment

TRANSPUPILLARY THERMOTHERAPY

• Used as solitary or adjuvant therapy

• Exert both a direct effect and probably increase susceptibility to the effects of chemotherapy

• The diode laser (810 nm) is used to provide hyperthermia.

• Direct application to the surface increases the tumor ’s temperature to the 45°–60° Celsius range and has a direct cytotoxic effect, which can be augmented by both chemotherapy and radiation

CRYOTHERAPY

• Applied under direct visualization with a triple freeze–thaw technique

• Typically, laser photoablation is chosen for posteriorly located tumors and cryoablation for more anteriorly located tumors

BRACHTHERAPY

• Using a radioactive plaque

• For anterior tumour if there is no vitreous seeding, • and in resistance to chemotherapy

EXTERNAL BEAM RADIOTHERAPY• Retinoblastoma is radio-sensitive• Globe salvage rates are excellent, with up to 85%

of eyes being retained • Visual function is often excellent and limited only

by tumor location or secondary complications• Complications:• The association of germline mutations of the RB1 gene with

a lifelong increase in the risk of second, independent primary malignancies

• Midface hypoplasia, radiation-induced cataract, and radiation optic neuropathy and retinopathy

• Evidence suggests that combined-modality therapy that uses lower-dose radiotherapy coupled with chemotherapy may allow for increased globe conservation with decreased radiation morbidity

ENUCLEATION

• The definitive treatment for retinoblastoma, providing, in most cases, a complete surgical resection of the disease

• Indications:• >50% of the globe involvement• orbital or optic nerve involvement is suspected• anterior segment involvement is present• neovascular glaucoma is present• there is limited visual potential in the affected eye

• Enucleation should be performed with minimal manipulation

• A section of optic nerve at least 10 mm should be obtained

EXTRAOCULAR EXTENSION

• External beam radiotherapy is indicated when there is tumour extension to the cut end of the optic nerve at enucleation, or extension through the sclera

• Adjuvant chemotherapy consisting of a 6-month course of CEV is given subsequent to enucleation at some centres if there is retrolaminar or massive choroidal spread

DIFFERENTIAL DIAGNOSES

• Persistent fetal vasculature• Coats disease• ROP• Toxocariasis• Uveitis• Vitreoretinal dysplasia• Trilateral retinoblastoma (pinealoblastoma)

SPONTANEOUS REGRESSION

• Retinoblastoma is one of the more common malignant tumors to undergo complete and spontaneous necrosis (although this is rarely recognized with active disease)• It’s recognized clinically after involutional

changes such as phthisis have occurred• Incidence is unknown• Mechanism is not understood, but its histologic

appearance is diagnostic

PROGNOSIS

• The most important risk factor associated with death is extraocular extension of tumor