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## **Meet the editor**

Professor G. Kumaramanickavel, MD, has worked extensively in ophthalmic genomics for more than two decades and has contributed significantly to the progress in the area of ocular genetics both nationally and internationally. He has worked on both single gene (retinoblastoma, corneal dystrophies, retinitis pigmentosa) and complex disorders (age-related macular degeneration,

diabetic retinopathy, glaucoma), particularly in the area of gene mapping and was successful in identifying ocular genes. As a Fogarty Visiting Associate in 1997-98, he worked at the National Eye Institute, National Institute of Health, United States of America. Between 1992-96 he was a Research Fellow at the University of Otago, Dunedin, New Zealand. He is currently the Research Director at two eye hospitals in India – Narayana Nethralaya, Bangalore and Aditya Jyot Eye Hospital, Mumbai. He teaches at the Chinese University of Hong Kong. He has published more than 85 articles including Nature Genetics, Human Molecular Genetics, American Journal of Medical Genetics and Genomics .

Contents

**Preface IX** 

**Part 1 Clinical Sciences 1** 

Chapter 2 **Second Malignancies in** 

Shaum P. Bhagat

Chapter 4 **Retinoblastoma –** 

**Part 2 Epidemiology 73** 

**Part 3 Basic Sciences 83** 

Luigi Bagella

Chapter 7 **Significance of** 

Chapter 6 **The Retinoblastoma Family** 

Jaya Padmanabhan

Chapter 5 **Epidemiology of Retinoblastoma 75**  Wilson O. Akhiwu and Alex P. Igbe

Chapter 1 **Review of Clinical Presentations of Retinoblastoma 3** 

**Retinoblastoma: The Real Problem 23**  Basil K. Williams Jr. and Amy C. Schefler

Claude Houdayer, Marion Gauthier-Villars, Laurent Castéra, Laurence Desjardins, François Doz and Dominique Stoppa-Lyonnet

**Protein p130 as a Negative Regulator of Cell Growth and Tumor Progression 85** 

**Retinoblastoma Protein in Survival and Differentiation of Cerebellar Neurons 109** 

Chapter 3 **Ototoxic Hearing Loss and Retinoblastoma Patients 39** 

**Genetic Counseling and Molecular Diagnosis 55** 

Onyekonwu Chijioke Godson

### Contents

#### **Preface XI**

#### **Part 1 Clinical Sciences 1**


#### **Part 2 Epidemiology 73**

	- **Part 3 Basic Sciences 83**

X Contents

Chapter 8 **Cytoskeletal Organization and Rb Tumor Suppressor Gene 131**  Yi-Jang Lee, Pei-Hsun Chiang and Peter C. Keng

#### Chapter 9 **Viral Oncogenes and the Retinoblastoma Family 155**  M. Geletu and L. Raptis

## Preface

Retinoblastoma is the first ever discovered tumor suppressor gene that opened a new avenue in the field of oncology leading to the identification of 35 tumor suppressor genes, till date in our genome. It is four decades since we know the two-hit hypotheses of Dr Alfred G Knudson and presently there is a huge amount of data available for us to completely comprehend the retinoblastoma gene and protein. However this reveals that there is more to learn and understand about its character and characteristics.

This book is an excellent compilation of both clinical and basic science information that meets the needs of a young clinician and a researcher at the same time. It also has abundant information on recent advances and cutting-edge knowledge in intracellular molecular cross-talking of retinoblastoma protein with various cellular viral-like proteins.

Looking into the details of this book, you will find that there is an excellent clinical description of the disease with adequate illustrations. The dreadful problem of second malignancies both ocular and non-ocular is dealt with elegantly. The ototoxic hearing loss in retinoblastoma patients provides greater insight into the disease, which would be a useful tool for practicing clinicians. For all levels of clinicians, whether entry, mid or senior, there is information on the genetic counseling and molecular diagnostics which are very useful. The epidemiology of retinoblastoma is a revelation for those both in clinics and research.

In understanding the molecular tumor biology of the disease, the role of RB protein in cell growth and tumor progression is extensively described. Interestingly a little known role of RB protein in the survival and differentiation of cerebellar neurons is discussed in great detail. The role of viral oncogenes and retinoblastoma family proteins is an exciting area that is teased out. The genetics of retinoblastoma is described quite elaborately as well.

#### **Dr. Govindasamy Kumaramanickavel**

Research Director, Narayana Nethralaya, Bangalore, Advisor - Research, Academics and Management, Aditya Jyot Eye Hospital, Mumbai India Visiting Associate, Ophthalmic Genetics and Clinical Services Branch, National Eye Institute, NIH USA

**Part 1** 

**Clinical Sciences** 

**Part 1** 

**Clinical Sciences** 

**1** 

*MBBS, FICS Nigeria* 

**Review of Clinical Presentations** 

A retinoblastoma is a neuroblastoma. It is a rare eye tumor of childhood that arises in the retina and represents the most common intraocular malignancy of infancy and childhood -**1**. It may occur at any age-**2**, but most often it occurs in younger children, usually before the age of two years. Most affected children are diagnosed before the age of five years-**1**,**3**. Intraocular tumours may exhibit a variety of growth patterns and is commonly seen in advanced countries. Extraocular retinoblastoma is common in developing countries because

In 60% of cases, the disease is unilateral (non hereditary) and the median age at diagnosis is two years. Retinoblastoma is bilateral (hereditary) in about 40% of cases with a median age at diagnosis of one year-**1**. Trilateral retinoblastoma is rare and refers to bilateral or unilateral retinoblastoma associated with an intracranial primitive neuroectodermal tumor in the pineal or suprasellar region-**6**. The median time interval from diagnosis of retinoblastoma to the development of a pineal region tumor was 24 months whereas the median time interval for the development of a suprasellar region tumor was 1 month-**6.**  Untreated, retinoblastoma is fatal. In the developing countries, retinoblastoma presents with advanced disease with resultant 5 year survival of less than 50%-**7** whereas patients present with intraocular disease in the developed countries due to availability of resources for early detection and treatment. The survival rate in these nations has improved from approximately 30% in the 1930s to over 90% in the 1990s -**8**,**9.** In the middle income countries, the survival rate is about 70% -**10.** Retinoblastoma occurs equally in males and

a. Leucocoria (white papillary reflex or cat's eye) is the most common accounting for about 60%- 80% of cases.-**1**,**4**,**5**. This is the most common type of presentation where

d. Proptosis follows orbital invasion. Secondary microbial infections are often present. This is a common type of presentation in most developing nations-**12** due mainly to

socioeconomic and cultural limitations resulting in delayed presentation -**10**

females and there is no predilection for any race or any particular eye-**11**.

there is high level of awareness such as in high income countries

**2. What are the common symptoms of retinoblastoma** 

c. Orbital inflammation is seen in cases of tumour necrosis-**4**

b. Strabismus occurs in about 20% of cases-**1**,**4**

**1. Introduction** 

of delay in diagnosis.-**4**,**5**.

**of Retinoblastoma** 

Onyekonwu Chijioke Godson

## **Review of Clinical Presentations of Retinoblastoma**

Onyekonwu Chijioke Godson *MBBS, FICS Nigeria* 

#### **1. Introduction**

A retinoblastoma is a neuroblastoma. It is a rare eye tumor of childhood that arises in the retina and represents the most common intraocular malignancy of infancy and childhood -**1**. It may occur at any age-**2**, but most often it occurs in younger children, usually before the age of two years. Most affected children are diagnosed before the age of five years-**1**,**3**. Intraocular tumours may exhibit a variety of growth patterns and is commonly seen in advanced countries. Extraocular retinoblastoma is common in developing countries because of delay in diagnosis.-**4**,**5**.

In 60% of cases, the disease is unilateral (non hereditary) and the median age at diagnosis is two years. Retinoblastoma is bilateral (hereditary) in about 40% of cases with a median age at diagnosis of one year-**1**. Trilateral retinoblastoma is rare and refers to bilateral or unilateral retinoblastoma associated with an intracranial primitive neuroectodermal tumor in the pineal or suprasellar region-**6**. The median time interval from diagnosis of retinoblastoma to the development of a pineal region tumor was 24 months whereas the median time interval for the development of a suprasellar region tumor was 1 month-**6.**  Untreated, retinoblastoma is fatal. In the developing countries, retinoblastoma presents with advanced disease with resultant 5 year survival of less than 50%-**7** whereas patients present with intraocular disease in the developed countries due to availability of resources for early detection and treatment. The survival rate in these nations has improved from approximately 30% in the 1930s to over 90% in the 1990s -**8**,**9.** In the middle income countries, the survival rate is about 70% -**10.** Retinoblastoma occurs equally in males and females and there is no predilection for any race or any particular eye-**11**.

#### **2. What are the common symptoms of retinoblastoma**


Review of Clinical Presentations of Retinoblastoma 5

f. Decrease in visual acuity-**12**

Fig. 5. Courtesy. inctr.ctisinc.com.

Fig. 6. Courtesy. www.jornallivre.com.br

presentation are the norms

**3. What are the common signs of retinoblastoma** 

cottage cheese if calcified. Vitreous seeding may be present

Fig. 7. Endophytic tumour. Courtesy. www.retinoblastomainfo.com

The clinical signs-**5**,**12** vary with the stage of the tumour at the time of presentation.

a. Early intraretinal tumour is a flat lesion which appears transparent or translucent. This type is commonly seen in high income countries where increase in awareness and early

b. Endophytic tumour projects from retinal surface toward the vitreous as a friable mass, frequently associated with fine blood vessels on its surface**-4**. The tumour resembles

Fig. 1. Left leucocoria in a child with retinoblastoma. Courtesy. Wikipedia

Fig. 2. Crossed eye in a child with retinoblastoma. Courtesy. Wikipedia

Fig. 3. Courtesy. www.arquivosdamorte.com

Fig. 4. Courtesy. projectmedishare.wordpress

Advanced extra ocular retinoblastoma in African and South American children above

e. Metastatic spread involves the brain/central nervous system, bones (especially skull bones and long bones), liver, spleen, Lymph nodes etc. This is worse in undeveloped economies due to late presentation and paucity of means of diagnosis -(-**1**,**4**,**5,12**)

f. Decrease in visual acuity-**12**

Retinoblastoma – An Update on Clinical, 4 Genetic Counseling, Epidemiology and Molecular Tumor Biology

Fig. 1. Left leucocoria in a child with retinoblastoma. Courtesy. Wikipedia

Fig. 2. Crossed eye in a child with retinoblastoma. Courtesy. Wikipedia

Fig. 3. Courtesy. www.arquivosdamorte.com

Fig. 4. Courtesy. projectmedishare.wordpress

Advanced extra ocular retinoblastoma in African and South American children above

e. Metastatic spread involves the brain/central nervous system, bones (especially skull bones and long bones), liver, spleen, Lymph nodes etc. This is worse in undeveloped

economies due to late presentation and paucity of means of diagnosis -(-**1**,**4**,**5,12**)

Fig. 5. Courtesy. inctr.ctisinc.com.

Fig. 6. Courtesy. www.jornallivre.com.br

#### **3. What are the common signs of retinoblastoma**

The clinical signs-**5**,**12** vary with the stage of the tumour at the time of presentation.


Fig. 7. Endophytic tumour. Courtesy. www.retinoblastomainfo.com

Review of Clinical Presentations of Retinoblastoma 7

Some patients diagnosed initially with possible retinoblastoma prove, on referral to ocular oncologists and radiologists, to have pseudoretinoblastoma-**4**,**5**,**13** and not retinoblastoma

Several classifications of retinoblastoma have been developed to assist in prediction of globe salvage with preservation of useful vision where possible. There are two classifications for

1. Reese-Ellsworth classification. Originally used to predict visual prognosis of affected eyes and globe salvage after external beam radiotherapy. It is still useful to compare

a. Solitary tumour less than 4 disc diameter in size at or behind the equator

a. Solitary tumour, 4 to 10 disc diameters in size at or behind the equator b. Multiple tumours , 4 to 10 disc diameters in size behind the equator

b. Solitary tumours larger than 10 disc diameters behind the equator

a. Multiple tumours, some larger than 10 disc diameters b. Any lesion extending to the anterior ora serrata

b. Multiple tumours, all less than 4 disc diameters in size all at or behind the equator.

**5. Differential diagnosis of retinoblastoma** 

Preseptal or orbital cellulitis in extraocular spread

**6. Classifications of retinoblastoma (Rb)** 

newer treatment modalities with older ones-**5**

intraocular retinoblastoma currently in use.

*Reese-Ellsworth classification of Retinoblastoma* 

a. Any lesion anterior to the equator

Myelinated nerve fibre, optic nerve glioma, medulloepithelioma

The more frequently encountered being Persistent hyperplastic primary vitreous

Coats disease Ocular toxocariasis Others include:

Retinopathy of prematurity

Organizing vitreous hemorrhage

Cataract

Uveitis

High myopia High anisometropia Retinal detachment

Group i. Favorable

Group ii. Favorable

Group iii. Doubtful

Group iv. Unfavorable

Group v. Very Unfavorable

c. Exophytic tumour. This grows from the retina outward into the subretinal space with progressive retinal detachment. It may become a multilobulated mass with overlying retinal detachment. As the orbital structures are invaded, proptosis increases. Sometimes the grossly detached retina may be visible just behind the clear lens. Presence of vitreous hemorrhage may make the fundus hazy. Clinically, they may resemble coats disease

Fig. 8. Fundus pictures of Retinoblastoma. Courtesy. journals.cambridge.org

Fig. 9. Large exophytic retinoblastoma with calcification producing exudative retinal detachment. Courtesy. Wikimedia commons

d. Occasionally, a retinoblastoma can assume a diffuse infiltrating feature characterized by a relatively flat infiltration of the retina by tumour cells without an obvious mass. In such cases, diagnosis may be more difficult and this pattern can simulate uveitis or endophthalmitis

#### **4. Less frequent signs of clinical presentations**


Retinoblastoma – An Update on Clinical, 6 Genetic Counseling, Epidemiology and Molecular Tumor Biology

c. Exophytic tumour. This grows from the retina outward into the subretinal space with progressive retinal detachment. It may become a multilobulated mass with overlying retinal detachment. As the orbital structures are invaded, proptosis increases. Sometimes the grossly detached retina may be visible just behind the clear lens. Presence of vitreous hemorrhage may make the fundus hazy. Clinically, they may

Fig. 8. Fundus pictures of Retinoblastoma. Courtesy. journals.cambridge.org

Fig. 9. Large exophytic retinoblastoma with calcification producing exudative retinal

d. Occasionally, a retinoblastoma can assume a diffuse infiltrating feature characterized by a relatively flat infiltration of the retina by tumour cells without an obvious mass. In such cases, diagnosis may be more difficult and this pattern can simulate uveitis or

a. Secondary glaucoma with or without buphthalmos-**4**,**13**. This is rare. Pain may be a

b. Anterior segment invasion-**4**, **13.** Multifocal iris invasion may be associated with hyphema and iris neovascularization; painful red eye with pseudohypopyon due to tumour seeding into the anterior chamber. This is mostly unilateral involvement with

c. Associated conditions. 13q deletion syndrome has retinoblastoma, dysmorphic features,

mental retardation which may be associated in some patients-**1**

detachment. Courtesy. Wikimedia commons

**4. Less frequent signs of clinical presentations** 

endophthalmitis

no family history.-**4**

feature

resemble coats disease

#### **5. Differential diagnosis of retinoblastoma**

Some patients diagnosed initially with possible retinoblastoma prove, on referral to ocular oncologists and radiologists, to have pseudoretinoblastoma-**4**,**5**,**13** and not retinoblastoma The more frequently encountered being

Persistent hyperplastic primary vitreous Coats disease Ocular toxocariasis Others include: Preseptal or orbital cellulitis in extraocular spread Cataract Retinopathy of prematurity Uveitis Myelinated nerve fibre, optic nerve glioma, medulloepithelioma Organizing vitreous hemorrhage High myopia High anisometropia Retinal detachment

#### **6. Classifications of retinoblastoma (Rb)**

Several classifications of retinoblastoma have been developed to assist in prediction of globe salvage with preservation of useful vision where possible. There are two classifications for intraocular retinoblastoma currently in use.

1. Reese-Ellsworth classification. Originally used to predict visual prognosis of affected eyes and globe salvage after external beam radiotherapy. It is still useful to compare newer treatment modalities with older ones-**5**

*Reese-Ellsworth classification of Retinoblastoma* 

Group i. Favorable


Group ii. Favorable


Group iii. Doubtful


Group iv. Unfavorable


Group v. Very Unfavorable

Review of Clinical Presentations of Retinoblastoma 9

Neovascular glaucoma or opaque media from hemorrhage to anterior chamber,

5. Classification encompassing entire spectrum of retinoblastoma disease stages-**17**.

This is an internationally proposed work to adopt a uniform staging system in which patients are classified according to the extent of the disease and the presence of overt extra

Stage 3. Regional extra ocular spread. a. Overt orbital disease. b. preauricular or cervical

Stage 4. Distant metastasis. 1. Hematogenous metastasis: a. Single lesion. b. Multiple lesions. 2. Central nervous system (CNS) extension: a. prechiasmatic lesion. b. CNS mass. c.

These are rare in developed countries such as the United States of America but unfortunately are still common in the developing nations due to delayed presentation and

Group Features

A Small tumour ≤3mm

Focal seeds C Subretinal seeds ≤3mm

Diffuse seeds. D Subretinal seeds > 3mm

ocular extension.

lymph node extension

Leptomeningeal disease.

b. Orbital invasion c. CNS involvement d. Distance metastasis.

a. Optic nerve involvement

lack of access to proper health facility-**4.**

Large tumour >3mm B Macular ≤3mm to foveola

Vitreous seeds ≤3mm

Vitreous seeds: > 3mm

vitreous or subretinal space

Juxtapappilary: ≤3mm to disc

Subretinal fluid: ≤3mm from the margin

Both subretinal or vitreous seeds ≤3mm

Both subretinal and vitreous seeds > 3mm E Extensive retinoblastoma occupying more than 50% or

Stage 0. Confined to the retina. Eye treated conservatively.

6. Extra-ocular retinoblastoma have 4 major types-**4**,**5**.

Stage 1. Confined to the retina. Eye enucleated, resected histologically.

Stage 2. Confined to the globe. Eye enucleated, microscopic residual tumour.


To predict the preservation of the eye using all modern therapeutic methods

Group A. Small tumours <3mm (about 0.1 inch) confined to the retina

Group B. Larger tumours confined to the retina

Group C. Localized seeding of the vitreous or under the retina <6.00mm (0.2inch) from the original tumour

Group D. Widespread vitreous or sub retinal seeding which may have total retinal detachment

Group E. No visual potential, eye cannot recover

#### **Others**

3. Philadelphia Practical Grouping System of Retinoblastoma Based on Clinical Features.- **14**

To quantify retinoblastoma and its associated features without need to refer to complex qualification criteria. Proceeding from the lowest to the highest grouping is meant to imply worse ocular prognosis. This is a simpler and newer classification to Reese-Ellsworth.


\*success after treatment with systemic chemotherapy with or without local consolidation is defined as avoidance of enucleation or need for external beam radiotherapy.
