**2. Retinoblastoma**

### **2.1. Epidemiology**

Retinoblastoma is the most common intraocular malignancy of childhood.[1] It represents about 4% of all pediatric malignancies, and affects approximately 1 in in 20,000 live births each year.[2] Most studies indicate that the incidence of retinoblastoma among various geographic populations is relatively constant. There is a 95% survival rate in developed countries, however the worldwide survival rate is closer to 50%. This is largely due to earlier detection in devel‐ oped countries, when the tumor is still confined to the globe. This is in contrast to underde‐ veloped areas where retinoblastomas are often diagnosed at an advanced stage, when they have already invaded the orbit or brain.

© 2013 Moran O' Keefe and ; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Moran and O' Keefe, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **2.2. Genetics**

Retinoblastoma arises from malignant transformation of primitive retinal cells before final differentiation. It can be inherited as a familial tumor in which the affected child has a positive family history of retinoblastoma or as a non-familial (sporadic tumor) in which the family history is negative. Approximately 94% of newly diagnosed retinoblastoma cases are sporadic, and 6% are familiar.

Retinoblastoma can be classified in 3 ways: familial or non-familial, heritable or non-heritable, unilateral or bilateral, however the 3 classifications are interrelated [3] Bilateral and familial retinoblastomas are caused by a germline tumor and are therefore heritable. Unilateral sporadic retinoblastoma is usually non-heritable, however it is estimated that 10-15% of children with unilateral sporadic retinoblastoma can have a germline mutation.

The retinoblastoma gene is located on the long arm of chromosome 13 (13q14). In order for retinoblastoma to develop, both copies of the gene at the 13q14 locus must be affected. If either the maternal or paternal copy of the gene that is inherited by an individual is defective, then the individual is heterozygous for the mutant allele. Tumor formation requires both alleles to be mutant or inactive- the concept of the "two-hit" hypothesis of Knudson. In familial cases, all the retinal precursor cells contain the initial mutation, and a when a second hit occurs, the cell undergoes malignant transformation. These children develop multifocal and bilateral tumors, and are at higher risk of non-ocular secondary tumors such as pinealoblastomas and osteosarcomas. In contrast, patients with unilateral sporadic retinoblastoma have normal chromosome structure elsewhere in the body and are at no higher risk of secondary tumors. In heritable retinoblastoma, the mutation is transmitted in 50%, but due to incomplete penetrance only 40% of offspring will be affected. If a child has heritable retinoblastoma, the risk to siblings is 2% if the parents are unaffected, and 40% if a parent is affected. In nonheritable cases the risk in each sibling and offspring is about 1%.

toma can have a diffuse infiltration pattern, which manifests as a relatively flat infiltration of

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The system was designed to predict outcome from treatment with external beam radiotherapy (EBRT), used interna‐

A. Solitary tumor, smaller than 4 disc diameters (DD), at or behind the equator. B. Multiple tumors, none larger than 4 DD, all at or behind the equator.

A. Solitary tumor, 4 to 10 DD at or behind the equator B. Multiple tumors, 4 to 10 DD behind the equator.

B. Solitary tumor, larger than 10DD behind the equator.

A. Massive tumors involving more than one half the retina.

tionally as the primary eye salvage treatment until introduction of chemotherapy in the 1980s.

the retina without an obvious tumor mass.

**Figure 1.** Leukocoria in a child with Retinoblastoma

**Group 1**: Very favorable for maintenance of sight

**Group 2**: Favorable for maintenance of sight

**Group 3**: Possible for maintenance of sight

**Group 4**: Unfavorable for maintenance of sight

**Group 5**: Very unfavorable for maintenance of sight

B. Vitreous seeding.

**Table 1.** Reese-Ellsworth Classification

A. Any lesion anterior to the equator.

A. Multiple tumors, some larger than 10 DD. B. Any lesion extending anteriorly to the ora serrata.

Genetic testing using DNA analysis of the patient's tumor can help to identify those with a germline or heritable mutation. Heritable tumors account for approximately 40% of tumors with the remainder being non-hereditary.

#### **2.3. Presentation and clinical features**

Presentation is usually within the first year of life if the tumor is bilateral or second year of life if the tumor is unilateral. Clinical features vary according to time of presentation. Leukocoria is the most common presenting feature (60%) and may be first noticed in family photographs. (Figure 1.) Strabismus is the next most common form of presentation (20%); therefore dilated fundal examination is mandatory in all cases of childhood strabismus. Retinoblastoma may also present with chronic uveitis, orbital inflammation, secondary glaucoma, or orbital invasion in advanced cases. Metastatic disease before the detection of ocular involvement is rare.

The growth pattern of retinoblastoma can be endophytic, exophytic, and intraretinal. Exo‐ phytic tumors grow from the retina outwards into the subretinal space, whereas endophytic tumors grow inward from the retina towards the vitreous cavity. Occasionally the retinoblas‐

**Figure 1.** Leukocoria in a child with Retinoblastoma

**2.2. Genetics**

28 Telemedicine

and 6% are familiar.

Retinoblastoma arises from malignant transformation of primitive retinal cells before final differentiation. It can be inherited as a familial tumor in which the affected child has a positive family history of retinoblastoma or as a non-familial (sporadic tumor) in which the family history is negative. Approximately 94% of newly diagnosed retinoblastoma cases are sporadic,

Retinoblastoma can be classified in 3 ways: familial or non-familial, heritable or non-heritable, unilateral or bilateral, however the 3 classifications are interrelated [3] Bilateral and familial retinoblastomas are caused by a germline tumor and are therefore heritable. Unilateral sporadic retinoblastoma is usually non-heritable, however it is estimated that 10-15% of

The retinoblastoma gene is located on the long arm of chromosome 13 (13q14). In order for retinoblastoma to develop, both copies of the gene at the 13q14 locus must be affected. If either the maternal or paternal copy of the gene that is inherited by an individual is defective, then the individual is heterozygous for the mutant allele. Tumor formation requires both alleles to be mutant or inactive- the concept of the "two-hit" hypothesis of Knudson. In familial cases, all the retinal precursor cells contain the initial mutation, and a when a second hit occurs, the cell undergoes malignant transformation. These children develop multifocal and bilateral tumors, and are at higher risk of non-ocular secondary tumors such as pinealoblastomas and osteosarcomas. In contrast, patients with unilateral sporadic retinoblastoma have normal chromosome structure elsewhere in the body and are at no higher risk of secondary tumors. In heritable retinoblastoma, the mutation is transmitted in 50%, but due to incomplete penetrance only 40% of offspring will be affected. If a child has heritable retinoblastoma, the risk to siblings is 2% if the parents are unaffected, and 40% if a parent is affected. In non-

Genetic testing using DNA analysis of the patient's tumor can help to identify those with a germline or heritable mutation. Heritable tumors account for approximately 40% of tumors

Presentation is usually within the first year of life if the tumor is bilateral or second year of life if the tumor is unilateral. Clinical features vary according to time of presentation. Leukocoria is the most common presenting feature (60%) and may be first noticed in family photographs. (Figure 1.) Strabismus is the next most common form of presentation (20%); therefore dilated fundal examination is mandatory in all cases of childhood strabismus. Retinoblastoma may also present with chronic uveitis, orbital inflammation, secondary glaucoma, or orbital invasion in advanced cases. Metastatic disease before the detection of ocular involvement is

The growth pattern of retinoblastoma can be endophytic, exophytic, and intraretinal. Exo‐ phytic tumors grow from the retina outwards into the subretinal space, whereas endophytic tumors grow inward from the retina towards the vitreous cavity. Occasionally the retinoblas‐

children with unilateral sporadic retinoblastoma can have a germline mutation.

heritable cases the risk in each sibling and offspring is about 1%.

with the remainder being non-hereditary.

**2.3. Presentation and clinical features**

rare.

toma can have a diffuse infiltration pattern, which manifests as a relatively flat infiltration of the retina without an obvious tumor mass.

**Group 1**: Very favorable for maintenance of sight

A. Solitary tumor, smaller than 4 disc diameters (DD), at or behind the equator.

B. Multiple tumors, none larger than 4 DD, all at or behind the equator.

**Group 2**: Favorable for maintenance of sight

A. Solitary tumor, 4 to 10 DD at or behind the equator

B. Multiple tumors, 4 to 10 DD behind the equator.

**Group 3**: Possible for maintenance of sight

A. Any lesion anterior to the equator.

B. Solitary tumor, larger than 10DD behind the equator.

**Group 4**: Unfavorable for maintenance of sight

A. Multiple tumors, some larger than 10 DD.

B. Any lesion extending anteriorly to the ora serrata.

**Group 5**: Very unfavorable for maintenance of sight

A. Massive tumors involving more than one half the retina.

B. Vitreous seeding.

The system was designed to predict outcome from treatment with external beam radiotherapy (EBRT), used interna‐ tionally as the primary eye salvage treatment until introduction of chemotherapy in the 1980s.

**Table 1.** Reese-Ellsworth Classification

**Figure 2.** Group V Tumor Left Eye on Presentation (December 2011) The eye was subsequently enucleated.

The International Classification for Intraocular Retinoblastoma is a newer staging system. It divides intraocular retinoblastomas into 5 groups, labeled A-E, based on the chances that the eye can be saved using current treatment options.

**Figure 3.** Fellow eye of the same patient: Multiple Tumors in Right eye at time of presentation (December 2011)

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Approximately 50% of patients diagnosed with possible retinoblastoma prove to have simulating conditions and not retinoblastoma. [4] Differential diagnoses include Persistent Hyperplastic Primary Vitreous, Coats disease, and ROP. It is essential to establish the diagnosis

Diagnosis is established through a combination of history and physical examination, usually requiring binocular indirect fundoscopy with scleral indentation. This is generally performed under anesthesia to precisely determine the number and location of tumors. An experienced examiner can establish the diagnosis based on the clinical appearance of the tumor. Ancillary diagnostic studies can be helpful if the diagnosis is uncertain. Ultrasonography and computed tomography can demonstrate the mass and detect presence of calcium. Magnetic resonance imaging is of value for assessing the optic nerve, orbit, and brain and evaluating spread outside

The primary objective in management of retinoblastoma is survival of the child, and secondly the preservation of the globe. After safety of the patient and the globe is establish‐ ed comes the focus on maintaining visual acuity. Treatment is tailored to each individual case, and there are several options. Intraocular retinoblastoma continues to be managed

**2.4 Differential diagnosis**

**2.5 Diagnosis**

the globe.

of retinoblastoma prior to commencing treatment.

**3. Management of retinoblastoma**


**Table 2.** International Classification of Retinoblastoma

**Figure 3.** Fellow eye of the same patient: Multiple Tumors in Right eye at time of presentation (December 2011)
