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Disease Entity

The most common intraocular malignancy of childhood is lethal if untreated.


Retinoblastoma is an intraocular malignancy. It is the most common intraocular malignancy of childhood. Worldwide incidence is reported to range from 1 in 15,000 to 35,000 live births per year. This malignancy usually develops at an early age. Immature cells committed to cone differentiation represent the origin. For decades, it has been known that there is a genetic component to this condition. The retinoblastoma susceptibility gene RB1 encodes a protein with a regulatory function in the cellular growth cycle. It is located on the subband 13q14.2. On presentation, 60% of cases are unilateral. The average age of presentation is 13-15 months. It occurs equally in males and females.


Both alleles of the retinoblastoma gene have to be inactivated are required for tumor development. The Rb gene is a tumor-suppressing gene. Knudson described the "two-hit" mechanism. If the first mutation occurs in the germline cells, the patient has hereditary retinoblastoma (2/5 of cases). If it occurs in somatic cells it is nonhereditary retinoblastoma. The second mutation occurs in somatic cells. The germline mutations can be transmitted (familial cases), or present de novo. Approximately 6% of new cases of retinoblastoma have a positive family history. In hereditary cases, the risk of developing retinoblastoma is transmitted as an autosomal dominant trait with high penetrance (90%).

Risk Factors

Two active copies of the retinoblastoma gene are normally carried in human cells. In patients with retinoblastoma, an initial mutation inactivates one copy of the gene. This may occur in a somatic cell (nonhereditary retinoblastoma), or in a germline cell (hereditary retinoblastoma). Tumor cells have an inactive or absent second, homologous copy of the retinoblastoma gene. Determining whether or not the initial mutation is in the germline of the affected patient helps to determine the risk to other family members. Affected patients who do not have a germinal mutation do not transmit a mutation to their offspring. In general, unilateral tumors are sporadic and nonhereditary, but this is not always the case. About 15% of unilateral cases occur in individuals who have germline mutations. Hereditary retinoblastoma is 90% penetrant.

General Pathology

In the 1950's, the Reese-Ellsworth classification system was developed to estimate the visual prognosis of affected eyes:

Group 1: Very Favorable

   a. Solitary tumor less than 4 disc diameter (DD) in size, at or behind equator.
   b. Multiple tumors, none over 4 DD in size, all at or behind equator.

Group 2: Favorable

   a. Solitary tumor, 4 to 10 DD in size, at or behind equator.
   b. Multiple tumors, 4 to 10 DD in size, behind equator.
Group 3: Doubtful

   a Any tumor anterior to equator.
   b. Solitary tumor, larger than 10 DD, behind equator.

Group 4: Unfavorable

   a. Multiple tumors, some larger than 10 DD in size.
   b. Any lesion extending anteriorly to the ora serrata.

Group 5: Very Unfavorable

   a. Massive tumor involving over half the retina.
   b. Vitreous seeding.


Because treatments were less successful decades ago than they are now, this classification system has less utility today. Also this classification system did not take into account whether or not the macula was involved. However, anatomic classification still has value.

International Classification for Intraocular Retinoblastoma that is used in the current Children’s Oncology Group treatment studies, as well in some institutional studies, has been shown to assist in predicting those who are likely to be cured without the need for enucleation or external-beam radiation treatment:

  • Group A: Small intraretinal tumors (< 3mm) away from foveola and disc.
  • Group B: Tumors > 3mm, macular or juxtapapillary location, or with subretinal fluid.
  • Group C: Tumor with focal subretinal or vitreous seeding within 3mm of tumor.
  • Group D: Tumor with diffuse subretinal or vitreous seeding > 3mm from tumor.
  • Group E: Extensive retinoblastoma occupying >50% of the globe with or without neovascular glaucoma, hemorrhage, extension of tumor to optic nerve or anterior chamber.

The classic appearance of retinoblastoma is of one or multiple nodular masses. These masses are white or cream colored and often have associated vascularization. The vitreous may be clear, have focal haze or diffuse haze (tumor seeding). There are two primary clinical patterns of retinoblastoma growth. If the tumor grows forward into the vitreous it is known as an endophytic tumor. These often show vitreous seeding which can progress to involvement of the anterior chamber, glaucoma and inflammation. When the tumor shows a growth pattern below the retina (subretinal) they are called exophytic tumors. These tumors can cause retinal detachments and may spread to the choroid and optic nerve. If untreated, these tumors continue to grow and fill the eye. Pain and inflammation can produce an appearance similar to endophthalmitis. Extraocular spread can occur and can be mistaken for preseptal or orbital cellulitis. Spread can also occur along the optic nerve into the brain. Bone is the preferred site for hematogenous metastases. The pineal gland may also display tumor, and this is known as trilateral retinoblastoma (the pineal gland is often referred to as the 'third eye'). This can produce hydrocephalus. Spontaneous regression of retinoblastoma occurs, but is rare. When tumor regresses after treatment, it can appear as a white, calcific mass or appear translucent and resemble fish flesh. When eyes with retinoblastoma are enucleated, the ocular pathologist evaluates the tissue to determine if the cut end of the optic nerve is free from tumor. Other key observations include whether or not the choroid is involved and whether or not there is any other evidence of extraocular tumor extension.


Retinoblastoma cells are small and stain blue with hematoxylin and eosin (H&E) stain. Rings of cells forming a lumen are known as Flexner-Wintersteiner rosettes. They are characteristic but not mandatory to make a diagnosis of retinoblastoma. Fleurettes are formed by cells undergoing photoreceptor differentiation. Calcification is common in these tumors. Necrosis is also very common, and occurs when the tumor outgrows its vascular supply. H&E staining of necrotic cells apears pink.

Primary prevention

Screening of all newborns for this condition is of limited value because many cases are not congenital. Certainly newborn screening would be worthwhile in offspring or siblings of patients with retinoblastoma. Offspring and siblings of affected patients require regular screening examinations in childhood. Genetic counseling for families with known retinoblastoma can help to determine whether other family members are at risk. Affected patients with the hereditary form of the condition are at increased risk for nonocular tumors later in life.

The American Academy of Pediatrics policy statement on Red Reflex Examinations in Neonates, Infants, and Children, recommends all neonates, infants, and children should have an examination of the red reflex before discharge from the neonatal nursery and during all subsequent routine health supervision visits. All infants or children with an abnormal Bruckner reflex or absent red reflex require immediate referral to an ophthalmologist skilled in pediatric examinations.


Early diagnosis of a retinoblastoma can maximize the patient's visual prognosis as well as their survival rate. For those who examine newborns, infants, and children, this diagnosis must always be in the differential for any child who presents with strabismus, leukocoria, a red eye, or a cellulitis-like picture. A careful history of present illness, family history, and thorough ophthalmic examination (as well as appropriate ancillary studies) are critical for prompt diagnosis.


The clinician must specifically inquire about a family history of blindness, an eye tumor, childhood malignancy, or an enucleation. Leukocoria and/or strabismus are the most common presentations of retinoblastoma, and the parent should be asked if either of these has been noted. Often parents will arrive with photographs which capture a white reflex (leukocoria). If known, the duration of time from discovery of the leukocoric reflex to presentation in the Ophthalmologist's office should be documented. The results of any ancillary testing done prior to your initial consultation with the family should be obtained.

Physical examination

Age-appropriate acuity testing should be performed monocularly. External examination should rule out proptosis or signs of an orbital cellulitis. Since the second most common presentation of retinoblastoma is strabismus, all patients who present with strabismus should receive a dilated funduscopic examination. The third most common presenting sign of retinoblastoma is intraocular inflammation, so the physicial examination should look for ciliary injection, pseudohypopyon, or signs of secondary glaucoma. The red reflex test should be performed, and the presence or absence of an afferent pupillary defect should be determined. The red reflex test is performed in a dimly lit or dark room with a direct ophthalmoscope or a retinoscope from a distance of about 1-1.5 feet from the patient. As mentioned earlier, a dilated fundusopic examination is critical. The funduscopic findings will differ depending on the type of tumor (endophytic or exophytic), the size(s) and location(s) of the tumor(s), and whether or not there is vitreous seeding or extension to the choroid or anterior chamber.


The most common presenting sign is leukocoria. This is often noticed by the parents in photographs as a white pupil light reflex or asymmetric reflexes. The second most common presentation is strabismus. Therefore, all children with strabismus should receive a dilated funduscopic examination at their initial visit. The third most common presentation is intraocular inflammation. Ciliary injection, a pseudohypopyon, or secondary glaucoma can all occur. Retinoblastoma presentation in an older child may masquerade as orbital cellulitis, uveitis, endophthalmitis, and or hyphema or vitreous hemorrhage. 

The vitreous may be clear. If the vitreous is seeded, one may find a hazy, diffuse appearance, or larger tumor aggregates. Endophytic tumors may grow and fill the vitreous. Exophytic tumors grow subretinally and may cause a retinal detachment.

Dysmorphic features, growth and mental retardation can occur in up to 5% of cases. The dysmorphic features include prominent eyebrows, broad nasal bridge, bulbous tip of nose, large mouth with a thin upper lip and long philtrum, microretrognathia, low-set ears, short neck, widely spaced nipples, and mental deficiency.


Most cases of retinoblastoma are painless and the child does is asymptomatic. If intraocular inflammation is present, then ciliary injection and possibly secondary glaucoma can occur. In this case, the child would have pain and photophobia.

Clinical diagnosis

Differentiating retinoblastoma from other conditions such as Coat's disease, persistent fetal vasculature (PFV), or toxocariasis can be a clinical challenge. PFV eyes tend to be microphthalmic and unilateral. In Coat's disease the eye may be full of a mass of material with associated neovascularization. The exudate in Coat's disease is more yellow than white because of the presence of cholesterol. Coat's disease is typically unilateral. The presence of intraocular calcium would favor a diagnosis of retinoblastoma over the aforementioned entities. B-scan ultrasound and CT can aid in the diagnosis by helping to decide if the lesion is calcified.

Diagnostic procedures

An examination under anesthesia is often necessary to confirm the diagnosis of retinoblastoma as well as determine the exact location and extent of the tumor(s) and tumor staging. Additional testing would include ultrasound (especially if a cataract limits the funduscopic view). Ultrasound can help define tumor height and thickness as well as determine whether or not there is an associated retinal detachment and calcification. Computerized tomography (CT), can help demonstrate the presence or absence of calcium deposits and help define the size of the tumor. Magnetic resonance imaging (MRI) is often performed to look for optic nerve involvement and also to evaluate for the possibility of trilateral retinoblastoma. Bone marrow examination or lumbar puncture may also be performed in patients where there is concern of extraocular extension to rule out brain or bone metastases.

Laboratory test

Aqueous levels of lactate dehydrogenase (LDH) can be measured, although this test is no longer considered useful.

Differential diagnosis

Leukocoria should immediately make the clinician think of retinoblastoma. However, the differential diagnosis includes other entities such as a cataract, Coat's disease, retinopathy of prematurity, toxocariasis, choroidal coloboma, vitreous hemorrhage, myellinated retinal nerve fibers, or an off-angle photograph. Corneal opacities can also produce a white reflex but this can be easily differentiated by clinical inspection. A leukocoric reflex can also occur with other retinal tumors, a retinal detachment, or retinal dysplasia.


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General treatment

The general concepts in the treatment of retinoblastoma are to preserve life, preserve the eye, and preserve vision in that order. Minimizing side effects and complications of treatment is also of paramount importance. Early treatment options including enucleation and external beam radiation have been augmented with other treatment options, including systemic chemotherapy, intra-arterial direct chemotherapy, cryopexy, laser photocoagulation, hyperthermia and plaque irradiation.

Medical therapy

Systemic chemotherapy treatment of retinoblastoma is a constantly evolving field. It is often used in conjunction with other modalities of treatment. Commonly used agents include vincristine, etoposide, and carboplatin. Chemotherapy is used to shrink intraocular retinoblastoma, and also for cases with orbital extension. The use of chemotherapy can improve ocular salvage rates and visual function. It can also reduce the risk of radiation-related second malignancies.

Medical follow up

Regular screening examinations are indicated in offspring of affected patents and siblings, Even patients with monocular tumors can have a germ-line mutation. Therefore, complete retinal examinations of the unaffected eye are necessary. In younger children, these are often performed under anesthesia. The affected eye also needs to be closely followed, looking at tumor growth or regression and any associated complications. A typical schedule would require examinations under general anesthesia every 3-6 months until age 3, followed by awake examinations thereafter.


In patients with advanced bilateral retinoblastoma, traditionally the more severely affected eye has been enucleated, while the less severely affected eye has undergone external beam irradiation. In cases where only one eye harbors tumor, enucleation is usually considered when the tumor is large and there is poor vision potential. More recently chemoreduction has changed this paradigm to allow more eyes to be saved. When an eye is enucleated for retinoblastoma, it is imperative that enough optic nerve is removed as well so that the cut end is free from tumor. Focal laser treatments can be used to treat these tumors in conjunction with chemotherapy and cryotherapy. The effectiveness of focal laser therapy is inversely related to tumor height.

Surgical follow up

Patients who have an eye enucleated will continue to be followed to ensure there is no evidence of tumor in the other eye. They can receive an ocular prosthetic. External beam irradiation treatments were typically given over the course of 3-4 weeks, but this form of treatment is less commonly used today. Patients who undergo any form of eye sparing treatment need frequent followup examinations. Tumor regression is followed closely, documenting the appearance, size, location and number of tumors during each examination. Patients with hereditary retinoblastoma are at increased lifetime risk of developing a variety of malignancies throughout the body. The most common secondary tumor is osteosarcoma. Other tumors include pineal tumors, fibrosarcoma, and melanoma. Also patients who have been treated with radiation are at higher risk for secondary tumors in the field of treatment. Therefore long term followup of these patients is mandatory.


Untreated retinoblastoma grows continuously, filling the eye with tumor. Retinal detachment occurs with exophytic tumors. Enlarging tumors can cause an inflamed and painful eye with possible glaucoma. The picture can appear similar to endophthalmitis. Further progression can cause tumor to spread extraocularly, masquerading as an orbital cellulitis. Tumor can extend directly along the optic nerve to involve the brain. Bone and marrow are the preferred sights for hematogenous spread. Patients with bilateral retinoblastoma are at risk for pineal gland involvement (trilateral retinoblastoma). As stated earlier in this article, patients with hereditary tumors are at increased lifetime risk for a variety of cancers. If pathologic review of an eye enucleated for a retinoblastoma shows tumor involving the lamina cribrosa, mortality rates are higher. This is true even if the transected end of the nerve is free of tumor. Eyes that are preserved are at risk for diminished vision from the tumor itself, retinal detachment, or amblyopia. Complications from treatment occur as well. Patients who received external beam irradiation are at risk for the development of secondary tumors within the field of treatment. Radiation optic neuropathy and retinopathy can occur. Patients can experience severe dry eye and also develop cataracts. Radiation can also effect growing orbital bones, producing facial hypoplasia. Chemotherapeutic agents are known to produce numerous potential side-effects. These include lowered immune status, increased incidence of secondary malignancies, and infertility. Cryotherapy can cause retinal thinning and retinal holes. This can be followed by retinal detachment, vitreous hemorrhages, tumor seeding and cataract. Laser treatments can be associated with iris burns, vitreous hemorrhage, and tumor break with vitreous seeding.


If left untreated, the mortality rate of retinoblastoma is about 99%. The major factor in mortality rates for patients with retinoblastoma is whether or not the tumor is confined to the eye. Extraocular spread increases mortality rates markedly. If there are tumor cells at the cut end of the optic nerve (with an enucleation), the mortality rate is much higher. Even if tumor is in the lamina cribrosa but the cut end of the optic nerve is free of tumor, mortality rates are elevated. However, when tumor is confined to the globe when enucleated, survival rates are greater than 92%. Retaining visual function depends on the tumor size and location. About half of children with bilateral disease undergoing conservative treatment have an acuity of 20/40-20/200 in at least one eye.

Additional Resources (FAQ section on retinoblastoma)


1.American Academy of Pediatrics policy statement- Red Reflex Examination in Neonates, Infants, and Children. Pediatrics 2008;122(6) 1401-1404.

2.Arbetman A, Abdala M, Fandino A, et al. Clinical, Cytogenetic, and Molecular Testing of Argentine Patients with Retinoblastoma. J AAPOS 1998;2:102-107.

3.Hamel P, Budning AS, Heon E, et al. Focal Therapy in the Management of Retinoblastoma: When to Start and When to Stop. J AAPOS 2000;4:334-337.

4.Hall LS, Ceisler E, Abramson DH. Visual Outomes in Children with Retinoblastoma. J AAPOS 1999;3:138-142.

5.Abramson DH. Retinoblastoma 1990: diagnosis, treatment and implications. Pediatr Ann 1990;19:387-95.

6.Shields CL, De Potter P, Himelstein BP, et al. Chemoreduction in the initial reduction of intraocular retinoblastoma. Arch Ophthalmol 1996;114:1330-8.

7.Ibarra MS and O'Brien JM. Is Screening for Primitive Neuroectodermal Tumors in Patients With Unilateral Retinoblastoma Necessary? J AAPOS 2000;4:54-6.

8.Karcioglu ZA, Abboud EB, Al-Mesder SA, et al. Retinoblastoma in Older Children. J AAPOS 2002;6:26-32.

9.Shields JA, Shields CL. Ocular tumors. A Text and atlas. Philadelphia, PA: Saunders; 1992. p.311-12.

10.Desjardins L, Chefchaouni MC, Lumbroso L, et al. Functional Results After Treatment of Retinoblastoma. J AAPOS 2002;6:108-11.

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