27 Retinoblastoma

10.1055/b-0037-149085

27 Retinoblastoma

Carol L. Shields and Jerry A. Shields

27.1 Introduction

Retinoblastoma is the most common intraocular cancer of childhood. ¹ ^, ² ^, ³ ^, ⁴ It represents approximately 4% of all pediatric malignancies. It is estimated that 250 to 300 new cases of retinoblastoma are diagnosed in the United States each year and 7,000 cases are diagnosed annually worldwide. This serious ocular malignancy can manifest covertly with painless leukocoria and can threaten survival of the patient. ² ^, ³ If untreated, retinoblastoma can lead to death within 1 to 2 years. Advanced disease with massive tumor, invasive into surrounding structures, has the greatest risk for metastasis. Worldwide, survival parallels economic development as retinoblastoma survival is approximately 30% in Africa, 60% in Asia, 80% in Latin American, and 95 to 97% in Europe and North America. ⁴

Large continents like Asia manage approximately 4,000 patients with retinoblastoma yearly and Africa has approximately 2,000 patients annually. ⁴ Reasons for the poor survival associated with retinoblastoma in undeveloped nations relate to late detection of advanced retinoblastoma, often presenting with orbital invasion or metastatic disease, and the lack of chemotherapy. In Brazil, the mean age at presentation for retinoblastoma is approximately 25 months, compared to 18 months or less in the United States. ⁵ It has been reported that Brazilian families delay seeking medical care for a mean of 6 months, and the delay was longer if the symptom was only strabismus of an eye with retinoblastoma (lag time: 9 mo) compared to if the symptom was leukocoria (lagtime: 6 mo) or tumor mass (lag time: 2 mo). ⁵

27.2 Basic Genetics

Retinoblastoma affects approximately 1 infant in 15,000 to 20,000 live births in the United States each year. ¹ ^, ² ^, ⁴ Most studies indicate that the incidence of retinoblastoma among the various geographic populations is relatively constant. The role of environmental influences in the development of this malignant intraocular tumor remains unclear. Prior to the 1860s, before the role of enucleation in the management of retinoblastoma was known, most cases of retinoblastoma proved fatal. At that time, little was suspected about the inheritance patterns of this tumor because few patients survived to reproductive age. Later, as more patients survived and had children of their own, more evidence arose suggesting the hereditary nature of retinoblastoma. It is now known that retinoblastoma can be inherited as a familial tumor, in which the affected child has a positive family history of retinoblastoma, or as a nonfamilial (sporadic) tumor in which the family history is negative for retinoblastoma. All patients with familial retinoblastoma are at risk to pass the trait to their offspring.

Retinoblastoma is classified in four different ways: familial or sporadic, bilateral or unilateral, heritable or nonheritable, and germline or somatic. Our preference is germline or somatic. It is recognized that bilateral and familial retinoblastoma are caused by a germline mutation and are, thus, a heritable tumor. Unilateral sporadic retinoblastoma is usually not heritable, but approximately 10 to 15% of children with unilateral sporadic retinoblastoma have a germline mutation. Genetic testing of the patient’s tumor and peripheral blood can help identify those with a germline mutation.

The retinoblastoma gene is located on the long arm of chromosome 13 (13q14). It is a large 4.73 kilobase message. An intact gene protects against expression of retinoblastoma. It is believed that the gene is a recessive suppressor gene and may play a role in cell growth and development. In order for retinoblastoma to develop, both copies of the gene at the 13q14 locus must be lost, deleted, mutated, or inactivated. If either the maternal or the paternal copy of the gene that is inherited by an individual is defective, then that individual is heterozygous for the mutant allele. Tumor formation requires both alleles of the gene to be mutant or inactive. These two mutations correlate to the two “hits” (two-hit hypothesis) theorized by Knudson in 1971. ⁶ Knudson proposed that the development of retinoblastoma was caused by two complementary chromosomal mutations. Each genetic event could occur randomly with a frequency of 2 × 10^– ⁷ per year. Therefore, in familial cases of retinoblastoma, all cells in the body are predisposed to possible tumor development since a germline mutation (“first hit”) has been inherited in all cells of the body, including the ovaries and testes. This explains the high incidence of second nonocular tumors, such as osteosarcoma, soft tissue sarcoma, and cutaneous melanoma seen in patients with familial retinoblastoma or bilateral sporadic retinoblastoma. The offspring in cases of familial retinoblastoma are likewise predisposed because their germinal mutation will be passed on. In contrast, in most cases of unilateral sporadic retinoblastoma, the “two hits” occur during development of the retina and both “hits” are somatic mutations. The rest of the body theoretically carries no higher risk to develop other tumors because these patients presumably have normal chromosomal structure elsewhere in the body.

27.2.1 Genetics: 13q Deletion Syndrome

The 13q deletion syndrome can manifest by several phenotypic abnormalities. Many patients have minimal or no visible abnormality. The characteristic findings include some degree of the following dysmorphic features: microcephaly, broad prominent nasal bridge, hypertelorism, microphthalmos, epicanthus, ptosis, protruding upper incisors, micrognathia, short neck with lateral folds, large prominent low-set ears, facial asymmetry, imperforate anus, genital malformations, perineal fistula, hypoplastic or absent thumbs, toe abnormalities, and psychomotor and mental retardation. The midface of patients with 13q deletion is notable for prominent eyebrows, broad nasal bridge, bulbous tipped nose, large mouth, and thin upper lip.

27.2.2 Genetic Counseling Regarding Future Offspring

When counseling the patient and family about the possibility of future children developing retinoblastoma, it is critical to know if the child or family carries a germline mutation for the retinoblastoma gene. Those patients with bilateral retinoblastoma and those with a family history of retinoblastoma can be assumed to have a germline mutation. These children are at a 50% risk of passing this gene to future children. The retinoblastoma gene is about 80% penetrant so that only 40% of their offspring will manifest the clinical findings of the gene and some offspring may only be carriers of the gene without developing retinoblastoma. All children with retinoblastoma should be offered genetic counseling and testing. A recommended screening protocol for newborn children with family history of retinoblastoma is listed in Table 27-1. ⁷

Table 27.1 Screening protocol for newborn children with family history of retinoblastoma
Age of baby	Examination period
Birth	First examination by 2 wk of age
Birth–3 mo	Every 1 mo
3 mo–1 y	Every 2 mo
1–2 y	Every 3 mo
2–3 y	Every 4 mo
3–4 y	Every 6 mo
Source: Data based on Moll et al. ⁷
Note: Using this protocol, familial retinoblastoma can be detected in 50% of cases by 2 months of age, 85% by 6 months, and nearly 100% by 12 months.

27.3 Life-Threatening Problems

Children with retinoblastoma are at risk for three important life-threatening problems including metastasis from retinoblastoma, intracranial neuroblastic malignancy (trilateral retinoblastoma), and second primary tumors.

27.3.1 At Risk for Metastases

Retinoblastoma metastasis, when it occurs, generally develops within 1 year of the diagnosis of the intraocular tumor. Those at greatest risk for metastasis show features of retinoblastoma invasion beyond the lamina cribrosa in the optic nerve, in the choroid (>2 mm dimension), in the sclera, in the orbit, or in the anterior chamber. ⁸ ^, ⁹ ^, ¹⁰ Eyes with invasion of the optic nerve or choroid generally demonstrate large retinoblastoma (over 15 mm greatest dimension) along with elevated intraocular pressure and total retinal detachment. ¹¹ ^, ¹² Patients with evidence of invasive retinoblastoma should be treated with chemotherapy for 6 months to prevent metastases. Honavar et al demonstrated that high-risk eyes showed reduction in metastases from 24% in those without preventative chemotherapy to 4% in those treated with chemotherapy. ⁸ Kaliki et al demonstrated that the use of vincristine, etoposide, and carboplatin for high-risk eyes was nearly uniformly effective. ⁹

Pearls

Eyes at high risk for retinoblastoma are those with

postlaminar optic nerve invasion.
choroidal invasion >3 mm.
any combination of optic nerve and choroidal invasion.
anterior segment invasion (possible risk).

Affected patients need six cycles of additional chemotherapy to prevent metastasis.

27.3.2 At Risk for Neuroblastic Intracranial Malignancy (Trilateral Retinoblastoma)

There is an association of neuroblastic intracranial malignancy in patients with the hereditary form of retinoblastoma, most often manifesting as pineoblastoma or other parasellar tumors. ¹³ ^, ¹⁴ ^, ¹⁵ ^, ¹⁶ ^, ¹⁷ The pineoblastoma is identical to retinoblastoma from an embryologic and pathologic standpoint. This association of midline intracranial pineal tumors and suprasellar/parasellar neuroblastic tumors with bilateral retinoblastoma has been termed “trilateral” retinoblastoma. ¹³ Loss of function of the retinoblastoma gene is believed to confer an increased susceptibility to developing these intracranial tumors. Trilateral retinoblastoma is found in approximately 3% of all children with retinoblastoma. ¹⁶ Those patients with bilateral or familial disease are at greatest risk, with 5 to 15% developing this finding. ¹⁶ Hence, patients with bilateral or familial retinoblastoma are advised to undergo screening for pineoblastoma using magnetic resonance imaging (MRI) twice yearly for the first 5 years of life. In some cases, the intracranial tumor precedes the diagnosis of retinoblastoma. Unlike other second tumors, the pineoblastoma usually occurs during the first 5 years of life, whereas second tumors often take many decades to develop. Unfortunately, pineoblastoma is often fatal.

Systemic chemoreduction for retinoblastoma can prevent trilateral retinoblastoma. ¹⁸ ^, ¹⁹ ^, ²⁰ In a study of 100 patients with hereditary retinoblastoma, trilateral retinoblastoma was found in no patient who received chemoreduction, and it would have been expected in 5 to 15 patients. ¹⁸ Additional evidence in the chemoreduction era indicates that pineoblastoma is rare and that chemoreduction might be preventing incipient malignancy. ²⁰ Others believe that the avoidance of external beam radiotherapy is the main reason for reduction in the frequency of trilateral retinoblastoma. ²¹ ^, ²² It should also be recognized that pineal gland enlargement might not be a solid tumor and may represent a benign cyst. ²⁰ ^, ²³

27.3.3 At Risk for Second Primary Cancers

Another important aspect of genetic counseling concerns the development of new genetically related cancers in survivors of bilateral or heritable retinoblastoma. Children with retinoblastoma have approximately a 5% chance of developing another malignancy during the first 10 years of follow-up, 18% during the first 20 years, and 26% within 30 years. ²⁴ The 30-year cumulative incidence is about 35% or even higher for those patients who received radiation therapy (external beam therapy) compared to an incidence rate of 6% for those patients who avoided radiation. Osteogenic sarcoma, often involving the femur, is most common, but other tumors such as spindle cell sarcoma, chondrosarcoma, rhabdomyosarcoma, neuroblastoma, glioma, leukemia, sebaceous carcinoma, squamous cell carcinoma, and malignant melanoma have also been recognized. Patients who survive a second tumor are at risk for a third, fourth, and even fifth nonocular tumors. ²⁵

27.4 Clinical Features of Retinoblastoma

The clinical features of retinoblastoma vary depending on the extent of tumor. In the United States, an evaluation of 1,265 patients revealed that the most common presenting signs included leukocoria (56%), strabismus (24%), and poor vision (8%). ²⁶ Further study on a cohort of 1,196 eyes found a median age at presentation of 15 months with 51% male, 49% female, 53% unilateral, and 47% bilateral. ²⁷ Zhao et al from China reviewed 470 eyes and found leukocoria (47%) as the most common presenting sign. ²⁸ Presentations of retinoblastoma differ. In a report from Sudan, ²⁹ buphthalmos (56%) and leukocoria (32%) were the most common presenting signs; in a study from Mali, ³⁰ proptosis (55%), leukocoria (38%), strabismus (6%), and buphthalmos (2%) were reported. Efforts are underway internationally to educate clinicians, nurses, patients, and entire populations for improvement in retinoblastoma detection.

The clinical manifestations of retinoblastoma vary with the stage of the disease at the time of recognition. In its earliest clinical stage, a small retinoblastoma under 2 mm in basal dimension appears ophthalmoscopically as a subtle, transparent, or slightly translucent lesion in the sensory retina. ² ^, ³ ^, ³¹ Slightly larger tumors lead to dilated retinal blood vessels that feed and drain the tumor. Some larger tumors show foci of chalk-like calcification that resemble cottage cheese. A retinoblastoma of any size can produce leukocoria. The larger tumors more often present with leukocoria. This white pupillary reflex is a result of reflection of light from the white mass in the retrolental area.

Retinoblastoma growth patterns are divided into intraretinal, endophytic, and exophytic. Intraretinal tumors are limited to the substance of the retina. Endophytic retinoblastoma grows from the retina inward toward the vitreous cavity. Hence, it is characterized by a white hazy mass with obscuration of the retinal blood vessels. Because of its friable nature, an endophytic tumor can seed the vitreous cavity and anterior chamber and simulate endophthalmitis. An exophytic retinoblastoma grows from the retina outward into the subretinal space. Such tumors produce a progressive retinal detachment, with the retina often displaced anteriorly behind a clear lens. An exophytic retinoblastoma can clinically resemble Coats’ disease or other forms of exudative retinal detachment. Occasionally, a retinoblastoma can assume a diffuse infiltrating pattern, characterized by a relatively flat infiltration of the retina by tumor cells without an obvious mass. ³² In such cases, the diagnosis can be more difficult and simulate uveitis or endophthalmitis. Less frequently, the presenting feature can be pseudohypopyon due to tumor seeding in the anterior chamber, hyphema secondary to iris neovascularization, vitreous hemorrhage, or signs of orbital cellulitis.

27.5 Classification of Retinoblastoma

There have been several classifications ³³ ^, ³⁴ ^, ³⁵ ^, ³⁶ ^, ³⁷ ^, ³⁸ proposed for intraocular retinoblastoma including the Reese-Ellsworth Classification, ³⁴ Essen Classification, ³⁵ and Philadelphia Classification. ³⁶ The most commonly used current classification is the International Classification of Retinoblastoma ¹⁶ ^, ¹⁷ designed in Paris in 2003 and based predominantly on the presence and extent of subretinal and vitreous tumors seeds (Table 27-2). The International Classification of Retinoblastoma is practical and applicable specifically for chemotherapy outcomes as it has been found predictive of treatment success following intravenous chemotherapy (IVitC).

Table 27.2 The International Classification of Retinoblastoma
Group	Quick reference	Philadelphia version	Los Angeles version
A	Small Rb	Rb = 3 mm	Rb = 3 mm, at least 3 mm from the foveola and 1.5 mm from optic nerve. No seeding
B	Bigger Rb Macular Rb Juxtapapillary Rb Subretinal fluid	Rb > 3 mm or Macular location or Juxtapapillary location (<1.5 mm to disc) or SRF present	Eyes with no vitreous or subretinal seeding and retinal tumors of any size or location not included in group A. Small cuff of subretinal fluid = 5 mm from tumor margin
C	Contained (focal) seeds	Rb with SRS =3 mm from Rb or VS =3 mm from Rb	Eyes with focal vitreous or subretinal seeding and discrete tumor of any size or location. Seeding must be local, fine, and limited so as to be theoretically treatable with a radioactive plaque. Up to one quadrant subretinal fluid may be present
D	Diffuse seeds	Rb with SRS >3 mm from Rb or VS >3 mm from Rb	Eyes with diffuse vitreous or subretinal seeding and/or massive, nondiscrete endophytic or exophytic disease. Seeding more extensive than group C. Retinal detachment > 1 quadrant
E	Extensive Rb	Rb with Size >50% of globe or Neovascular glaucoma or Opaque media or Invasion of optic nerve, choroid, sclera, orbit, anterior chamber	Massive Rb with anatomic or functional destruction of the eye with one or more of the following: Neovascular glaucoma Massive intraocular hemorrhage Aseptic orbital cellulitis Tumor anterior to anterior vitreous face Tumor touching lens Diffuse infiltrating tumor Phthisis or prephthisis
Abbreviations: Rb, retinoblastoma; SRF, subretinal fluid; SRS, subretinal seeds; VS, vitreous seeds.

27.6 Leading Simulators of Retinoblastoma

The diagnosis of retinoblastoma is based on characteristic clinical features of a yellow-white retinal mass often with surrounding subretinal fluid, subretinal seeding, and vitreous seeding. Ancillary testing can confirm the diagnosis. Fine needle aspiration biopsy or open biopsy of retinoblastoma is not performed due to risk for local tumor dissemination. The diagnosis is established based on clinical features alone. Despite classic manifestations, retinoblastoma can display a spectrum of unusual features that overlap with other conditions (pseudoretinoblastomas) and can lead to diagnostic confusion. ³⁹

Accurate clinical diagnosis is important to avoid mistreatment, particularly with chemotherapy. In a large series of 2,775 eyes referred with possible retinoblastoma, retinoblastoma was confirmed in 2,171 (78%) eyes and a simulating lesion (pseudoretinoblastoma) in 604 (22%). ³⁹ Overall, the leading pseudoretinoblastoma lesions included Coats’ disease (40%), persistent fetal vasculature (PFV) (26%), and vitreous hemorrhage (5%) (Table 27-3). The pseudoretinoblastomas differed based on age at presentation. Of patients age =1 year, PFV (49%) was the most common pseudoretinoblastoma, whereas in children >2 years, Coats’ disease (60%) was most common (Table 27-3 and Table 27-4).

Table 27.3 Lesions referred with the diagnosis of possible retinoblastoma but proved to be other condition (pseudoretinoblastoma) in 604 consecutive patients based on age at presentation
	Patient age Number (% per diagnosis) [% per age group]
Pseudoretinoblastoma diagnosis	Mean, median [range] in y	0–1 y n = 283	>1 to 2 y n = 57	>2 to 5 y n = 89	> 5 y n = 175	All ages n = 604
Coats’ disease	6, 4 [0.2–30]	58 (24) [20]	33 (14) [58]	54 (22) [61]	99 (41) [57]	244 (100) [40]
Persistent fetal vasculature	2, 1 [0.2–24]	138 (87) [49]	6 (4) [11]	6 (4) [7]	8 (5) [5]	158 (100) [26]
Vitreous hemorrhage	1, 1 [0.5–8]	21 (78) [7]	3 (11) [5]	1 (4) [1]	2 (7) [1]	27 (100) [5]
Toxocariasis	8, 8 [1–18]	1 (5) [<1]	0 (0) [0]	7 (32) [8]	14 (64) [8]	22 (100) [4]
Familial exudative vitreoretinopathy	7, 7 [0.6–16]	5 (28) [2]	1 (6) [2]	1 (6) [1]	11 (61) [6]	18 (100) [3]
Rhegmatogenous retinal detachment	5, 1 [0.5–24]	10 (56) [4]	0 (0) [0]	3 (17) [3]	5 (28) [3]	18 (100) [3]
Coloboma	3,1 [0.3–11]	9 (53) [3]	1 (6) [2]	3 (18) [3]	4 (24) [2]	17 (100) [3]
Astrocytic hamartoma	8, 6 [0.5–28]	3 (20) [1]	1 (7) [2]	3 (20) [3]	8 (53) [5]	15 (100) [2]
Combined hamartoma	4, 2 [0.5–16]	4 (27) [1]	5 (33) [9]	1 (7) [1]	5 (33) [3]	15 (100) [2]
Endogenous endophthalmitis	5, 5 [0.2–11]	2 (20) [<1]	0 (0) [0]	2 (20) [2]	6 (60) [3]	10 (100) [2]
Myelinated nerve fibers	4, 4 [0.5–11]	3 (33) [1]	0 (0) [0]	2 (22) [2]	4 (44) [2]	9 (100) [1]
Congenital cataract	3, 1 [0.2–12]	5 (63) [2]	1 (13) [2]	0 (0) [0]	2 (25) [1]	8 (100) [1]
Peripheral uveoretinitis	3, 2 [0.5 to 6]	3 (43) [1]	1 (14) [2]	0 (0) [0]	3 (43) [2]	7 (100) [1]
Retinopathy of prematurity	2, 2 [0.8–7]	3 (43) [1]	2 (29) [4]	1 (14) [1]	1 (14) [<1]	7 (100) [1]
Nonrhegmatogenous retinal detachment	1, 1 [0.6–4]	4 (80) [1]	0 (0) [0]	1 (20) [1]	0 (0) [0]	5 (100) [<1]
Medulloepithelioma	4, 4 [2–5]	0 (0) [0]	1 (25) [2]	3 (75) [3]	0 (0) [0]	4 (100) [<1]
X-linked retinoschisis	2, 1 [0.6–7]	3 (75) [1]	0 (0) [0]	0 (0) [0]	1 (25) [<1]	4 (100) [<1]
Vitreoretinal tuft	3, 1 [0.6–8]	2 (67) [<1]	0 (0) [0]	0 (0) [0]	1 (33) [<1]	3 (100) [<1]
Incontinentia pigmenti	4, 4 [2–6]	0 (0) [0]	1 (50) [2]	0 (0) [0]	1 (50) [<1]	2 (100) [<1]
Juvenile xanthogranuloma	1, 1 [0.7–0.8]	2 (100) [<1]	0 (0) [0]	0 (0) [0]	0 (0) [0]	2 (100) [<1]
Norrie’s disease	1, 1 [0.7–0.8]	2 (100) [<1]	0 (0) [0]	0 (0) [0]	0 (0) [0]	2 (100) [<1]
Vasoproliferative tumor	10, 10 [3–17]	2 (100) [<1]	0 (0) [0]	0 (0) [0]	0 (0) [0]	2 (100) [<1]
Choroidal osteoma	3	0 (0) [0]	0 (0) [0]	1 (100) [1]	0 (0) [0]	1 (100) [<1]
Morning glory disc anomaly	1	1 (100) [<1]	0 (0) [0]	0 (0) [0]	0 (0) [0]	1 (100) [<1]
Retinal capillary hemangioma	16	1 (100) [<1]	0 (0) [0]	0 (0) [0]	0 (0) [0]	1 (100) [<1]
Retrolental fibrosis	2	0 (0) [0]	1 (100) [2]	0 (0) [0]	0 (0) [0]	1 (100) [<1]
Toxoplasmosis	1	1 (100) [<1]	0 (0) [0]	0 (0) [0]	0 (0) [0]	1 (100) [<1]
Source: Data gathered from Shields et al. ³⁹
Note: (%) indicates percentage per diagnosis, by row.
[%] indicates percentage by age group, by column.

Table 27.4 Differentiation of Coats’ disease from retinoblastoma
Feature	Coats’ disease	Retinoblastoma
Age of onset (mean)	5 y	1.5 y
Gender
Male	76%	50%
Female	24%	50%
Laterality
Unilateral	95%	60%
Bilateral	5%	40%
Family history of disease	0%	10%
Eye findings
Anterior chamber	Rare cholesterol crystals	Rare white cells with hypopyon
Iris neovascularization	Present in 8%	Present in 17%
Cataract	Absent	Absent
Vitreous	Murky	White fluffy seeds
Retinal vessels	Irregular dilation with telangiectasia Remain visible throughout course Most commonly seen temporally	Tortuous, but regular dilation towards a mass Disappear into tumor Occur in quadrant of tumor
Retinal exudation	Present	Absent
Retinal mass	Absent	Present
Retinal gliosis	Present, forming subretinal scar	Absent
Retinoschisis/macrocyst	Present	Absent
Subretinal fluid	Present, with exudation and refractile cholesterol	Present, with white subretinal seeds
Diagnostic testing
Ultrasonography	Retinal detachment Subretinal echoes minimal Rare calcification at level of retinal pigment epithelium	Retinal detachment Subretinal echoes from seeds Calcification within retinal tumor and shadowing
Optical coherence tomography	Retinal detachment Retinal edema Subretinal deposits	Retinal detachment Solid intraretinal mass arising in middle to outer retina Normal retina draped over mass.
Computed tomography	Retinal detachment	Retinal detachment with calcified retinal mass
Magnetic resonance tomography	Retinal detachment	Retinal detachment with enhancement of retinal mass

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