RETINOBLASTOMA

Click to edit Rahul Yadav style Master subtitle

11408032 SRM University Chennai

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Introduction

Eyes:Eyesareorgansthat

detectlightand convert it to electro-chemical impulses in neurons.

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Lens:- projects images on the retina. Retina:-a light sensitive layer of cells, is responsible for translating light images into electrical impulses. Cornea:- the clear portion of the front of the eye that bends light rays through the pupil to the lens. Pupil:- is the black opening in the iris. Iris:- the colored ring of tissue, regulates the amount of light entering the eye by 4/29/12 adjusting the size of the pupil.

How eyes work ?

Light rays reflect off the object and into the eye where they are refracted by the cornea and focussed by the lens on to the retina, the optic nerve then carries the messages to the brain and an image is formed.

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RETINOBLASTOMA
Retinoblastoma is a rare type of eye cancer that usually develops in early childhood, typically before the age of 5.

Also known as RB Retinal Glioblastoma Retinal Glioma

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Epidemiology
Retinoblastoma is the most common primary intraocular malignancy (eye cancer) of childhood. It arise in neural layer of Retina. Usually appears between birth and 4 years of age. Has one of the best cure rates of all childhood. cancers (95-98%). If left untreated, will spread to other body parts that would be fatal.

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 Spread

of Retinoblastoma in extraocular region

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History
Retinoblastoma was documented in children more than 2,000 years ago
Rudolph

Virchow first described the tumor that would eventually be called retinoblastoma in 1864.

Historical image showing Gordon Isaacs, the first patient treated with the linear accelerator ( external beam radiation therapy) for retinoblastoma in 1957.

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Classification
o

Two types-Sporadic and Familial Sporadic -Non-genetic i.e. no history of disease within family. -70% of all cases of Rb -Usually Unilateral i.e. present in only one eye. Familail -Genetic. 4/29/12 - 20% of all cases of Rb.

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Leukocoria:-

-A white eye reflex that occurs when light is shown into pupil. -Often noticed as white spot in affected eye when photograph is taken with a flash. -Normal eye gives red reflex in photograph.

Symptoms
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 Leukocoria

in child with Retinoblastoma

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Contd.
o

Strabismus:-

-a misalignment of the eyes; when both eyes do not appear to be looking in same direction -also called "wandering eye" or "crossed-eyes. Two types eso and exo.
Red o

Eye-

Pain or redness around the eye(s) and Poor vision

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Other Rb Tumor Forms

Sec

glucoma. Orbital and optical nerve inflammation Proptosis Pseudohypopyon

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Prevalence
Seen in 1:14000 to 1:20000 live births around the world. No racial predilection. occurs equally in males and females. More than 95% of patients treated for retinoblastoma in the are cured More than 90% of patients retain at least one eye. More than 80% of the children keep 20/20 vision

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Statistics
o

At Sankara Nethralaya we see roughly 80 100 new retinoblastoma cases of every year. In india nearly 300-400 cases of retinoblastoma are registered every year 5000 cases of RB are documentated every year around the World

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Famous celebrities
Peter Falk (actor) was three years old he lost his eye to cancer.

Actor, Matthew Ashford's (Days of our lives) young daughter, Emma, was diagnosed with the disease and she also lost an eye.

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Retinoblastoma occurs due to mutations in a tumor suppressor gene (called RB1) located on chromosome 13q14.2. Two mutations (or gene changes) are necessary to "knock-out" this gene, and cause uncontrolled cell growth. It is unknown what causes the gene abnormality; it is most likely to be a random mistake during the copy process which occurs when a cell divides. Rb1 gene

Genetic basis of Retinoblastoma

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Molecular Biology of RB Gene

o

It spans 200 kilobases (kb) and is composed of 27 exons. Encodes a 4.7-kb messenger ribonucleic acid (mRNA) transcript The protein encoded,pRB is of 110 KDa,and have 928 amino acids. pRB regulates cell-cycle,so cell proliferation and acts as Tumor Suppressor.

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Contd.
o

pRB comprises - a nuclear localization signal - a potential phosphorylation site and most important, -A and B pocket domain. With these two domain pRB binds to E2F trnscription factors.

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How pRB acts as Tumour Suppressor? The pRB protein negatively regulates the cellular G1/S phase transition. Depophosphorylated pRB binds with family of transcription factor(E2Fs1, 2 and 3),and repress their transcriptional activity. E2F controls the expression of a group of genes whose products are required either for the G1-to-S transition itself or for DNA replication (e.g. DNA polymerase alpha).

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o o o

Contd. Thus cell-cycle is regulated. Phosphorylated pRB looses afinity for E2Fs. Cyclin-Cdk complex brings about phosphorylation of pRB.

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During normal cell cycle

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Mutation and Effects

o

May arise due to:-large scale deletion or translocation in chromosomal region(13q14 region) -splicing error. -point mutation. -small deletion in promoter region. -hypermethylation of CpG island in the promote region. -environmental effects. -binding of viral protein to pRB (SV40,Adeno,and human papilloma virus) Mutated pRb fails to bind to E2Fs,so loss of transcriptional control over cell proliferation.

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Contd. Unregulated cell division leads to tumour growth and carcinogenesis.

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Inheritance Pattern
o

Disease usually occurs sporadically but may show an autosomal dominant inheritance. Sporadic cases are of two types: Somatic mutants:- The genetic abnormality is in the retina so that the disease is not transmitted

(I)

(2) Germinal mutants:- These represent about 1O to 20 per cent. of sporadic cases. The genetic abnormality is in germinal cells -inherited to next generation -equally affects both sexes.
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Diagnosis o Simple eye examination:-The Red Reflex(for leukocoria) -The Corneal Light Reflex/Hirchberg test strabismus)
o

(for

Examination Under Anesthsia(EUA) - with the child under anesthesia, the pupils are dilated so the entire retina can be viewed and examined. Computed tomography scan- a CT scan of the head is a computerized X-ray that provides a very clear picture of the eyes,the surrounding tissue and the brain.

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 EUA

CT

scan of Retinoblastoma

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Contd. Magnetic resonance imaging (MRI)- a diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to produce detailed images of organs and structures within the body.

o o

Genetic or DNA testing(predictive testing)

Identifying theRB1gene mutation

-can be used to predict about child of next generation. -can be done indirectly by pedigree analysis or directly by Rsa-1 digestion of exon 21 product.

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PCR RFLP

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Differential diagnosis
1.Persistent

hyperplastic primary vitreous (PHPV): congenital developmental anomaly of the eye . .2.Coat's disease: a typically unilateral disease characterised by abnormal development of blood vessels behind the retina to mimic retinoblastoma .3.Toxocara canis: an infectious disease of the eye associated with exposure to infected puppies. 4.Retinopathy of prematurity(ROP): associated with low birth weight infants, it involves damage to the retinal tissue and 4/29/12 may lead to retinal detachment.

What are the possible treatments?

o

is

Laser Therapy:-performed with EUA,a powerful beam of light

focused through dilated pupuil,which destroy the cancerous tumour. -can be repeated if needed. o Cryotherapy:-is performed in conjunction with an EUA. -A probe (which looks like a pen) is placed on the sclera nearest to the tumor, using a very 4/29/12 cold

Contd.

Chemotherapy:-anti-cancer drugs are used which destroy tumour cells and stop their growth. 1Vincristine-is made from the periwinkle plant,causes cells 4/29/12 to

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Contd.
o

Enucleation:-eye ball is removed,is the last option when there is no other way to remove cancer. PDT:-Photodynamic therapy (PDT) is a recent approach for the treatment of small cancerous tumours, in which a dye is used (usually a tetrapyrrolic macrocycle),which absorbs light and generates cytotoxic reactive oxygen species leading to cellular damage)

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. . .continued

External beam radiationhas been used since

the early 1900's as a way to save the eye(s) and vision. Retinoblastoma is sensitive to radiation, and frequently the treatment is successful. The radiation treatment is performed on an outpatient basis five times per week over a 3 to 4 week stretch.

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 Cryotherapy

lasertherapy

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Movies
Marathi

Movie - Shwaas No Hollywood movie

video

on Retinoblastoma Video of intra ocular surgery

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References
o o o o o o o

www.cancer.org www.ChildrensCancerAssociation.org www.nci.nih.gov www.children-cancer.com www.eyecancer.com The cellular effects of E2F over expression, PMID: 8575214 Alterations in G1/S cell-cycle control contributing to carcinogenesis, PMID: 9616737 Molecular mechanisms controlling the cell cycle: fundamental aspects and implications for oncology,PMID: 4/29/12 11355576

Contd. o Towards a new treatment of retinoblastoma, PMID: 20569775 o www.retnoblastoma.com o www.eyecancer.md.org o Retinoblastoma www.rarediseases.org

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