AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Retinoblastoma is the most common primary ocular malignancy of childhood.

The first description of a tumor resembling retinoblastoma was by Peter Pawius of Amsterdam. He wrote of a malignancy invading the orbit, the temporal region, and the cranium, a picture now strongly suggestive of untreated retinoblastoma. The tumor was described to be filled with a "substance similar to brain tissue mixed with thick blood and like crushed stone."

In 1805, William Hey coined the term fungus haematodes, which he used to describe a fungating mass affecting the globe of the eye and destroying its internal organization.

In 1809, the Scottish surgeon James Wardrop pieced together the random isolated facts and observations of previous authors. Despite not having a microscope at his disposal, his meticulous dissection and astute interpretations of some of these eyes led him to conclude that in most instances the tumor arose from the retina. Wardrop documented the extension of the tumor to the optic nerve and brain. Later, he described metastasis to different parts of the body.

In 1836, Langenbech, Robin, and Nystin of Paris confirmed by microscopic studies that the tumor definitely arose from the retina.

In 1864, Virchow named it a glioma of the retina, supporting glial cells as the cell of origin of the tumor.

In 1891, Flexner of Johns Hopkins was first to notice rosettes within the tumor. A few years later in 1897, Wintersteiner concurred with Flexner and proposed the name neuroepithelioma noting its resemblance to rods and cones and traced one tumor to the photoreceptor cell layer. Presently, their names are attached to these rosettes.

Most cells comprising the tumor histologically resembled the cells of an undifferentiated retina of the embryo called retinoblasts. This resemblance prompted Veorhoff to coin the term retinoblastoma, which later was adopted by the American Ophthalmological Society in 1926 as a general term for this entity.

In 1970, Tso and colleagues established that the tumor arises from photoreceptor precursors.

Pathophysiology

The most widely held concept of histogenesis of retinoblastoma holds that it generally arises from a multipotential precursor cell (mutation in the long arm of chromosome 13 band 13q14) that could develop into almost any type of inner or outer retinal cell. Intraocularly, it exhibits a variety of growth patterns, which classically have been described, as outlined below. (See Causes for more information.)

Endophytic growth

Endophytic growth occurs when the tumor breaks through the internal limiting membrane and has an ophthalmic appearance of a white-to-cream mass showing either no surface vessels or small irregular tumor vessels. This growth pattern typically is associated with vitreous seeding wherein small fragments of tissue become separated from the main tumor. In some instances, vitreous seeding may be extensive allowing tumor cells to be visible as spheroid masses floating in the vitreous and anterior chamber, simulating endophthalmitis or iridocyclitis, and obscuring the primary mass. Secondary deposits or seeding of tumor cells into other areas of the retina may be confused with multicentric tumors.

Exophytic growth

Exophytic growth occurs in the subretinal space. This growth pattern often is associated with subretinal fluid accumulation and retinal detachment. The tumor cells may infiltrate through the Bruch membrane into the choroid and then invade either blood vessels or ciliary nerves or vessels. Retinal vessels are noted to increase in caliber and tortuosity as they overlie the mass.

Diffuse infiltrating growth

This is a rare subtype comprising 1.5% of all retinoblastoma. It is characterized by a relatively flat infiltration of the retina by tumor cells but without a discrete tumor mass. The obvious white mass seen in typical retinoblastoma rarely occurs. It grows slowly compared with typical retinoblastoma.

Frequency

United States

It is estimated that around 250-500 new cases of retinoblastoma occur in the United States yearly.

International

Worldwide, the incidence of retinoblastoma is recorded to be about 11 cases per million children younger than 5 years. A more commonly used estimate is 1 case of retinoblastoma per 18,000-30,000 live births, depending on the country.

In the Philippines, unpublished reports have estimated the incidence to be greater than 1 case of retinoblastoma per 18,000 live births.

Mortality/Morbidity

Survival rates for patients with retinoblastoma range from a reported 86-92%. However, this must be kept in the context of the retinoblastoma cancers. In actuality, the survival rate drops with each decade of life for patients with the genomic mutation. The genomic mutation is a gene mutation within every cell of the individual's body. These patients typically present with either bilateral disease or unilateral-multifocal (one eye with multiple distinctly separate tumor foci) disease. These individuals have a predisposition for developing second cancers later in life.

Mortality in these individuals is consequently much higher than those with somatic mutations (ie, affecting one retinal cell only and unilateral-unifocal disease). The greatest predictor of death is extraocular extension, either directly through the sclera or via extension along the optic nerve. Several of these topics are discussed further in later sections of this article.

Race

• There seems to be no racial predilection for retinoblastoma.
• No difference in incidence exists among blacks and whites.

Sex

• Studies show that there appears to be no significant difference in the incidence of retinoblastoma by sex for children aged 0-14 years.
• The estimated boys-to-girls ratio is reportedly 1.12:1.

Age

Retinoblastoma is diagnosed at an average of 18 months with 90% diagnosed before patients reach age 5 years.

• Children who are affected bilaterally are diagnosed at an average age of 13 months, while patients with unilateral retinoblastoma are diagnosed at an average age of 24 months.
• When a known family history of retinoblastoma exists, patients with bilateral retinoblastoma are diagnosed at an average age of 11 months.
• A few cases of retinoblastoma in adults (aged 20 y and older) have been reported in the literature. Some theorize that these lesions arise from a previously existing retinocytoma that underwent malignant transformation.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

At the time of initial examination, obtain a careful family history.

• Specifically ask parents about the occurrence of retinoblastoma in the family.
• Elicit a history of eye tumors, previous enucleation, or any malignancy in childhood from any of the family members.
• Only about 5% of patients who develop this disease have a positive family history. Most of the time, these are patients whose tumors are discovered earliest.
• A large number of patients with retinoblastoma (95%) have no previous family history, including those who have the bilateral hereditary form of the disease.

Physical

The clinical findings in all the stages of retinoblastoma are numerous and varied. Image 10 presents an overview of the presenting signs in retinoblastoma.

• Leukocoria (white pupillary reflex or cat's eye reflex) is the most common presenting sign, accounting for about 56.1% of cases.
• Strabismus, which occurs as a result of visual loss, is the second most common mode of presentation. Thus, funduscopic examination through a well-dilated pupil must be performed in all cases of childhood strabismus.
• Retinoblastoma can cause secondary changes in the eye, including glaucoma, retinal detachment, and inflammation secondary to tumor necrosis.
• • Pseudouveitis, with a red eye and pain associated hypopyon and hyphema, is a rare presentation. It is characteristic of an infiltrating type of retinoblastoma in which the tumor cells invade the retina diffusely without forming a discrete tumor mass.
  • Orbital inflammation mimicking orbital cellulitis may occur in eyes with necrotic tumors and does not necessarily imply extraocular extension.
• Proptosis is a more common presenting symptom in most underdeveloped countries.

Causes

Retinoblastoma is caused by the so-called retinoblastoma gene, which is a mutation in the long arm of chromosome 13.

• This gene name is actually a misnomer because it does not actively lead to retinoblastoma.
• The unaffected gene actually suppresses the development of retinoblastoma.
• When both homologous loci of the suppressor gene become nonfunctional by either deletion error or by mutation, retinoblastoma develops.
• A positive family history is present in 5-10% of children who develop this disease.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Persistent hyperplastic primary vitreous
Toxocariasis
Nematode endophthalmitis
Colobomas of choroid and disc
Uveitis
Congenital retinal fold
Retinal dysplasia
Retinal astrocytic hamartomas
Retinal capillary hemangiomatosis
Tumors other than retinoblastoma

To assist the clinician in coming up with a differential diagnosis cheat sheet, the following diseases have been categorized by presenting tumor:

Diseases presenting as an exophytic tumor

Coats disease
Toxocariasis
Choroiditis
Exudative retinitis
Choroidal hemangioma
Angiomatosis retinae
Retinal pigment epithelium proliferation

Diseases presenting as an endophytic tumor

Retinal hamartomas
Astrocytomas
Myelinated nerve fibers
Retinochoroiditis
Metastatic endophthalmitis

Diseases presenting with leukocoria

Cicatricial retinopathy of prematurity
Persistent hyperplastic primary vitreous
Retinal dysplasia
Toxocariasis
Pseudogliomas
Coats disease
Medulloepitheliomas
Retinal detachments
Late stage vitreous hemorrhage

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Blood counts and electrolyte determination as well as urinalysis and liver function tests are useful in excluding other conditions confused with retinoblastoma.
• Blood specimens should be taken not only from the patient but also from the parents and any siblings for DNA analysis, which could aid in genetic counseling.
• • There are direct and indirect methods in the analysis of the retinoblastoma gene. The direct method aims to find the initial mutation that precipitated the development of the tumor; then, it is determined whether that mutation is in the germline of the affected patient. Indirect methods can be used in cases where the initial mutation cannot be located or it is uncertain whether it exists.
  • Source of DNA to be evaluated directly are either from tumor cells or leukocytes.
  • Deletions or rearrangements of the retinoblastoma gene can be detected by either karyotyping or Southern blotting techniques.
  • Point mutations in the retinoblastoma gene can be detected by the following techniques: ribonuclease protection, denaturing gradient gel electrophoresis, single-strand conformation polymorphism, or direct DNA sequencing amplified by the polymerase chain reaction.
  • Retinoblastomas also may arise by hypermethylation of the promoter region of the retinoblastoma gene, which deactivates this gene but does not alter the DNA sequence. This also can be detected by Southern blot analysis.
  • Indirect methods of analysis of the retinoblastoma gene rely on DNA polymorphisms within this gene.
• Assays of aqueous humor enzyme levels could offer useful information to patients with suspected retinoblastoma. Lactate dehydrogenase (LDH) is a glycolytic enzyme that uses glucose as an energy source. It is present in high concentrations within metabolically active cells. Normally, its concentration in serum and aqueous humor is low and the ratio of aqueous humor to serum LDH is less than 1.0 in patients with ocular disease other than retinoblastoma. However, aqueous humor for eyes with retinoblastoma exhibits increased LDH activity expressed as an aqueous humor/LDH ratio of greater than 1.0

Imaging Studies

• Cranial and orbital computerized tomography provides a sensitive method for diagnosis and detecting intraocular calcification and shows intraocular extent of the tumor even in the absence of calcification. This neuroimaging technique is also invaluable in assessing the CNS anatomy, including the optic nerve, for possible extension of retinoblastoma.
• Ultrasonography is useful in distinguishing retinoblastomas from non-neoplastic conditions. It is also useful in detecting calcifications.
• MRI
• • MRI may be beneficial in estimating the degree of differentiation of retinoblastomas but is not as specific as computerized tomography because of its lack of sensitivity in detecting calcium.
  • Studies show that on T1-weighted images, the tumors usually have a low intensity and are usually difficult to distinguish from surrounding vitreous, but, on T2-weighted images, retinoblastoma tumors demonstrate very low intensity compared to vitreous. Calcification is more pronounced on T2 sequences.
  • MRI also is useful in identifying any associated hemorrhagic or exudative retinal detachment. This is seen as a localized subretinal area of higher signal intensity compared to vitreous on both T1- and T2-weighted sequences.
• X-ray studies: In areas of the world where ultrasonography and computerized tomography are not available, x-ray studies may be the only means of identifying intraocular calcium in patients with opaque media.

Other Tests

• Immunohistopathologic staining
• • The aim of immunohistochemical studies is to decide whether retinoblastomas come from a common progenitor cell capable of differentiation into either glial or neuronal cells or from neuron-committed cells.
  • Numerous variables alter the results in these studies. These variables include tissue fixation, staining procedures, specific areas taken into consideration, tumor cell differentiation, antigen expressivity, and age of tumor.
  • Caution is required when interpreting most immunohistochemical results because of the related controversies associated with these tests. An experienced immunopathologist is required to provide worthwhile results.
  • Immunohistochemical and biochemical studies show an S-antigen detected in well-differentiated retinoblastomas using immunoperoxidase staining of paraffin sections. Felberg and Donoso have performed several studies on this.
  • Bridges and colleagues performed biochemical assays and showed interphotoreceptor retinoid-binding protein (IRBP) in retinoblastoma. These findings suggested an embryonic origin of the cells.
  • Numerous contradictory studies providing evidence for a neuronal nature and differentiation exist.
• Transmission electron microscopy
• • Ultrastructural investigations have paved the way for more definitive descriptions of retinoblastoma. Research using this technology provided evidence of the presence of photoreceptor cell elements in retinoblastoma, and a strong evidence of retinoblastoma to human fetal retina has been demonstrated.
  • The ultrastructural findings of retinoblastoma investigations have been described previously.

Procedures

• Patients noted to have presenting signs of retinoblastoma should undergo prompt office examination.
• • Complete eye examination should be performed including an estimation of the patient's visual acuity for both eyes.
  • A dilated fundus examination with indirect ophthalmoscopy should be completed since ancillary diagnostic studies play only a secondary role when the fundus can be visualized clearly.
• Bone marrow aspiration and biopsy
• • A bone marrow aspiration and biopsy could be performed as well as lumbar puncture with cytocentrifuge examination for tumor cells. These may prove useful in the early diagnosis of distant spread since the primary mode of spread of retinoblastoma is hematogenous to the bone marrow and back through the optic nerve into the cerebrospinal fluid (CSF).
  • Results of a study by Moscinski et al recommends performing bone marrow and CSF evaluations only in patients with clinical, histologic, or radiologic evidence of local or systemic extension or in patients presenting with 1 R-E group V eye with retrolaminar or extrascleral extension of their tumor. They also recommend limiting follow-up bone marrow and CSF determinations to those patients who develop objective signs and symptoms of metastasis or recurrence.

Histologic Findings

The classic histologic findings of retinoblastoma are Flexner-Wintersteiner rosettes and less commonly fleurettes. A Homer-Wright rosette can be encountered, but they also are seen in other neuroblastic tumors.

Considerable variability exists in the histologic features. Some neoplasms display marked necrosis and prominent foci of calcification. Few show areas of glial differentiation.

Note: In an enucleated eye that is being prepared for gross examination and fixation for histopathologic examination, it is essential that adequate fixation is attained (fixation usually is complete within 48 h). Thorough fixation is especially important for eyes removed for retinoblastoma because the tumor is friable and may be spilled into the uvea or outside of the eye when the eye is sectioned, thereby confusing the assessment of the confinement of tumor to the interior of the eye (a feature that is important for the assessment of survival

Staging

The staging of retinoblastoma is currently in flux. The Reese-Ellsworth classification system was the most useful system when external beam radiation was the standard of treatment for eye salvage. However, now that chemotherapy has supplanted radiation, this classification system is not as predictive of outcome and survival. A Linn Murphree and colleagues have developed (and are in the process of refining) a new classification system. These classification systems are listed in Image 11.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Medical therapy should be directed toward complete control of the tumor and the preservation of as much useful vision as possible. Treatment usually is individualized to the specific patient.

• External beam radiation therapy
• • There is a high incidence of local control and minimal retinal, late effects with radiation doses of 4000-4500 cGy used with 200 cGy fractions. However, there is significant morbidity and mortality associated with external beam radiation therapy (EBRT). EBRT results in cessation of bone growth. Therefore, children with retinoblastoma who are treated with EBRT have significant midface hypoplasia (the younger the child when EBRT is instituted, the more dramatic the outcome). More importantly, EBRT has shown to increase the risk of developing second cancers almost 6-fold during the lifetime of these patients. Today, neoadjuvant chemotherapy (chemoreduction) has superseded EBRT in order to (hopefully) circumvent these terrible adverse effects of EBRT. Nevertheless, EBRT is still indicated in selected circumstances, as follows:
  • • For eyes with significant vitreous seeding
    • For children who have progression of disease while undergoing chemoreduction
    • For tumors extending up to or beyond the cut margin of the optic nerve of an enucleated eye (Such a case currently is debated as to the best method of treatment.
• Radioactive isotope plaques
• • Use of either radioactive 60 Co (cobalt), radioactive 125 I (iodine), which is presently the most used, radioactive 192 Ir (iridium), and radioactive 106 Ru (ruthenium)
  • Radioactive 125 I plaque treatment is recommended for treatment of one larger tumor or a limited number of moderately sized tumors ( <3) present in noncritical areas
  • Advantage - Locally directed treatment to the tumor minimizing radiation to the normal tissue
  • Disadvantage - Incomplete treatment, high dose to local sclera, significantly less irradiation for anterior lesions, and difficulty placing posterior plaques
• Chemotherapy
• • Primary neoadjuvant chemotherapy or chemoreduction has been the most significant recent advance in the treatment of retinoblastoma. This is typically the principle mode of treatment for eyes in intraocular groups C and D. However, our understanding of dose, duration, and end points are still evolving with this relatively new treatment modality.

    Prophylactic chemotherapy is recommended if there is a tumor in the optic nerve past the lamina cribrosa because these cases have a poor survival prognosis.

  • Use of neoadjuvant chemotherapy has the advantage of limiting the necessity for EBRT and reducing the possibility of EBRT-related complications.
  • Chemotherapy also may be used prior to EBRT as completed by Kingston and associates in an attempt to improve local control and visual outcome in children with group V tumors using carboplatin, etoposide, and vincristine, followed by 40-44 Gy of EBRT.
  • Shields and associates used carboplatin, etoposide, and vincristine chemotherapy, followed by cryotherapy, photocoagulation, and 125 I plaque treatment in an attempt to improve outcome for eyes with more advanced retinoblastoma commonly treated with enucleation.
  • Current studies completed by the Retinoblastoma Study Group show the promising use of chemotherapy (carboplatin, vincristine sulfate, and etoposide phosphate) as a primary mode of treatment in reducing tumor bulk, followed by various forms of local approaches (radiotherapy [external beam or plaque], cryotherapy, thermotherapy, and photocoagulation) that can be used for final tumor control.
  • Some reports suggest the addition of cyclosporine in combination with the chemotherapy regimen of carboplatin, etoposide, and vincristine. These reports showed that this addition enhances the efficacy of chemotherapy and eliminates the need for radiation.

Surgical Care

Surgical removal of the tumor has been the standard management of very unfavorable retinoblastoma cases.

• Enucleation
• • Enucleation is performed when there is no chance of preserving useful vision in an eye.
  • Patients generally requiring enucleation are those who present with total retinal detachments and/or the posterior segment is full of the tumor in which case it is clear the patient cannot retain any form of useful vision.
• Cryotherapy
• • Cryotherapy can be used primarily for small anteriorly located tumors, remote from the disc and macula but also may be indicated for recurrence after radiation therapy.
  • Cryotherapy is performed transsclerally. Under direct visualization, freezing is carried out until the ice ball incorporates the entire tumor. A refreeze-thaw cycle is repeated 3-4 times.
  • Complete disappearance of the tumor with a flat pigmented scar is the sign of successful treatment. This can be repeated if the tumor does not respond initially.
• Photocoagulation
• • Photocoagulation can be used as primary therapy for small posteriorly located tumors.
  • There is a danger of producing large field defects near the disc and decreased vision resulting from macular pucker by photocoagulation near the macula.
  • The technique is performed by placing a double row of confluent burns around each tumor using a photocoagulator.
  • It is important not to do direct treatment on the tumor itself because the light color of the tumor generally precludes absorption of sufficient energy and there is a danger of exploding the tumor with spread of viable tumor debris into the vitreous and other parts of the retina.
  • Successful treatment with photocoagulation takes weeks to evolve, which is a complete disappearance of the tumor and replaced with a flat area.
  • Photocoagulation also can be used for tumor recurrences after EBRT.
• Exenteration is still being performed especially in most underdeveloped countries when there is considerable extension of the tumor into the surrounding areas.

Consultations

Patients with retinoblastoma should be evaluated and treated by a team of medical professionals, including an ophthalmologist (preferably an ocular oncologist), pediatrician, oncologist, radiologist, and pathologist. Given that this is a relatively uncommon disease, patients should try to seek attention from physicians with subspecialty training and experience in retinoblastoma, and who are actively participating in organizations that explore up-to-date treatments for retinoblastoma.

• The pathologist plays a special role in the treatment of a patient with retinoblastoma. The surgical specimens should be evaluated with care to guide the clinicians with the appropriate postsurgical management.
• Appropriate consultations are needed to provide much needed information to each other. In some instances, frozen sections are requested after enucleation or exenteration.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Use of chemotherapeutic drugs should be limited to specific group of patients for whom the benefits outweigh the potential disadvantages.

Drug Category: Anticancer drugs

Used for management of metastasis but also used as adjuvant therapy for patients with high-risk retinoblastoma.

Drug Category: Immunosuppressants

The addition of cyclosporine in combination with chemotherapy regimen of carboplatin, etoposide, and vincristine reportedly have showed enhanced efficacy of chemotherapy.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Inpatient care is mostly supportive during the period of recuperation after surgery or during chemotherapy.
• Daily attention to the cleansing and dressing of a postenucleated eye or postexenterated orbit is necessary.

Further Outpatient Care

• Patients with treated retinoblastoma as well as siblings who are at risk of inheriting the tumor need to be observed indefinitely.
• Patients and siblings of patients in whom the risk of retinoblastoma cannot be ruled out by genetic studies should be observed with examination under anesthesia every 3-4 months until age 3-4 years. After which, they are examined under anesthesia every 6 months until age 5-6 years and then annually. At about age 8 years, most patients are able to tolerate a dilated fundus examination in the office without anesthesia and can be examined annually in the office thereafter.
• Periodic office examinations to check visual acuity, alignment, and general ocular health should be performed. The patient and parents should be questioned about and warned about signs of secondary nonocular tumors during these examinations.
• Formal examination under general anesthesia is completed 6 months after completion of radiation therapy.
• For classic regression patterns, see Image 12.
• As long as the tumor is not enlarging, it can be considered to be locally controlled by radiation therapy.

In/Out Patient Meds

• Only supportive medications during chemotherapy or after surgery are needed. These include antinauseating agents, broad-spectrum antibiotics, and painkillers.

Deterrence/Prevention

• Frequent ophthalmologic examination is indicated for children at elevated risk.
• Estimation of risk can be completed using molecular genetics.
• DNA testing can be a cost effective component of the care of patients with retinoblastoma and their relatives.
• Diagnosing the tumor as early as possible is important to prevent progression leading to metastasis and ultimately death.

Complications

• Secondary nonocular tumors can develop in survivors of retinoblastoma, in order of decreasing frequency: osteosarcoma, various soft tissue sarcomas, malignant melanoma, various carcinomas, leukemia and lymphoma, and various brain tumors. (See Special Concerns.)
• Cataract formation: Radiation doses of 800 cGy to the lens using dose rates of 150-300 cGy/min usually lead to cataract formation in 18 months to 3+ years.
• Vascular complications: Retinal vascular damage and hemorrhage may be seen after external beam radiation using 70-75 Gy with 200-350 cGy per fraction.
• Bone, dental, and soft tissue effects: Hypoplasia of bone and soft tissue structures after treatment with radiation doses exceeding 3500 cGy may occur. The maxillary molar tooth buds located high in the maxilla just inferior to the posterior apex of the orbit may become irradiated with treatment. Numerous reports of failure of tooth eruption have been noted in patients with retinoblastoma treated with irradiation.

Prognosis

• The prognosis in retinoblastoma is good where prompt medical care is available. The overall survival rate of retinoblastoma in the United States and Great Britain is presently greater than 85%.
• The cure rate is almost 90% if the optic nerve is not involved and enucleation is performed before the tumor passes through the lamina cribrosa.
• Survival rates decrease to 60% if the tumor extends beyond the lamina cribrosa even if the cut end of the nerve is free of tumor cells.
• Survival rates decrease to less than 20% if the tumor cells are found at the surgical transection sight.
• Death occurs secondary to intracranial extension. Treatment with EBRT results in an 85% cure rate.
• Visual preservation occurs in 90% of children with group I and II disease (Reese-Ellsworth classification); 30-40% for group IV and 10-15% for patients with advanced group V disease.
• Of patients previously treated with EBRT, 60% require further therapy with cryotherapy or photocoagulation.
• Of patients requiring treatment with EBRT, 20% eventually require enucleation.

Patient Education

• Genetic counseling for retinoblastoma
• • In 1979, Vogel published his review on the genetics of retinoblastoma in the journal of Human Genetics. He reviewed the likelihood for the recurrence of retinoblastoma in close relatives of a patient with the disease, based on clinical criteria (see Image 13). It is the physician's responsibility to inform the patient's family that retinoblastoma can be hereditary. The methods for screening and estimation of risks are highly improved with using molecular genetics techniques, although this sometimes can prove to be very expensive.
  • In a normal individual, there exist 2 copies of the retinoblastoma gene, 1 coming from each parent. However, in patients with retinoblastoma, one copy of the gene is inactivated by an initial mutation.
  • When the initial mutation arises from a somatic cell (retinal), the patient has the nonhereditary type of retinoblastoma and the relatives have a low risk for the disease. These individuals have 1 abnormal gene in all their cells, and the mutation in the other gene (in the retinal cell) allows the expression of the tumor.
  • When the initial mutation arises from the germline, the patient has the hereditary type of retinoblastoma and the relatives of the patient have a significant risk for retinoblastoma. In these individuals, both mutations occur only in the retinal cell that has become malignant.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Retinoblastoma is a rare but extremely important disease to the ophthalmologist since its misdiagnosis is one of the few errors in the practice of ophthalmology that can lead to the death of a child.

Special Concerns

• Adult retinoblastoma has been reported several times in the literature. Identifying this subgroup of patients with retinoblastoma is important. Clinicians should include retinoblastoma in the differential diagnosis of intraocular tumors occurring in older individuals.
• Parents and siblings of patients with retinoblastoma should be evaluated for untreated retinoblastoma or retinoma.
• Some recent reports have suggested that patients with retinoblastoma without neurologic abnormalities or evidence of extraocular extension do not require systemic metastatic evaluation (bone marrow and lumbar puncture).
• Third world concerns
• • It is unfortunate that in this day and age wherein greater than 90% of retinoblastoma cases are able to survive with appropriate treatment, neglected cases of highly advanced retinoblastoma are still seen in third world countries, particularly the Philippines.
  • Factors such as poverty, illiteracy, cultural beliefs, health-seeking behavior, politics, and public health information affect the patient's time of presentation to a health institution or a clinician.
  • In the Philippine General Hospital (PGH), the largest tertiary hospital in the Philippines, 1-3 new advanced cases of retinoblastoma are seen each month. Steps for globe preservation are attempted, but, in most instances wherein there is extensive tumor growth and extension, surgical debulking combined with radiotherapy and chemotherapy is the only logical route.
  • A retinoblastoma clinic has been set up at the PGH Department of Ophthalmology and Visual Sciences (1998) in an attempt to address the continuing needs of patients with retinoblastoma. In its initial year of operation, a total of 39 new retinoblastoma cases were seen. Linear follow-up care has improved, but the specialty clinic continues to experience funding and staffing problems.
• Retinocytoma
• • Retinocytomas are rare tumors that are composed entirely of benign-appearing cells with numerous fleurettes and show no evidence of necrosis or mitotic activity.
  • Some studies suggest that these lesions can reactivate and undergo malignant transformation.
  • Genetic implications of retinocytoma are the same as that of retinoblastoma.
  • Examine family members of patients with retinoblastoma closely for retinocytoma and if positive, follow up periodically throughout their lives.
  • Even patients without a family history of retinoblastoma but with a retinal lesion suggestive of retinocytoma should be monitored carefully.
• Trilateral retinoblastoma
• • These are cases of bilateral retinoblastoma associated with an ectopic intracranial retinoblastoma usually involving the pineal gland or the parasellar region.
  • Trilateral retinoblastomas contribute significantly to the overall mortality in patients with hereditary retinoblastoma in the first decade of life accounting for approximately 50% of deaths.
  • Screening efforts for patients with trilateral retinoblastoma should be directed to those at risk namely those patients with bilateral or multifocal disease and those with a positive family history.
  • Current recommendations in screening for trilateral disease uses gadolinium-enhanced MRI or computed tomography with contrast every 6 months up to age 5 years in patients with hereditary cases of retinoblastoma.
• Secondary malignancies
• • Studies show that up to 50% of patients who survive bilateral retinoblastoma develop secondary nonocular tumors during their lifetime.
  • Patients treated with EBRT appear to be at a much greater risk of developing second tumors. Dunkel et al demonstrated that by age 40 years 6% of those patients who did not receive EBRT had developed second primary malignant neoplasms as compared to 35% for those who did receive EBRT.
  • Patients and their siblings should be assessed periodically for any signs of developing tumors other than retinoblastoma.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Retinoblastoma, intraocular stage (leukocoria). History: NB, 1-year-old male from Quezon Province, Philippines, with chief complaint of opacity, left eye. Born full term spontaneous vaginal delivery (FTSVD) to a 27-year-old gravida 3, para 2 (2002) at home. Four months prior to admission (PTA), opacity was noted in the left eye (no consultation/medications). Five days PTA, consultation with an ophthalmologist. Examination: (+) leukocoria with visual acuity of central, steady, and maintained fixation on right eye, (-) dazzle on left eye; (+) Marcus Gunn (MG) reflex. Diagnostics: Ocular ultrasound was performed, revealing intraocular retinoblastoma. Management: Patient underwent enucleation of left eye. Examination under anesthesia of right eye: E/N retina. Histopathology: Retinoblastoma, intraocular stage left eye.
	View Full Size Image
Media type:  Photo

Media file 2:  Retinoblastoma, glaucomatous stage. History: AB, 2-year-old female from Marikina City, Philippines, with chief complaint of proptosis, right eye. The patient is an adopted child. Prior to admission (PTA), with child aged 6 months (time of adoption), surrogate mother noted an opacity in the right eye. No medical consultation. One year PTA, physician consultation; told AB had an "eye mass" and needed to see an ophthalmologist. No compliance. One month PTA, proptosis was noted in the right eye. Examination: Visual acuity (VA) of right eye is no light perception; VA of left eye is central, steady, and maintained fixation. Sensorium: Awake but irritable. Diagnostics: Intracranial extension on CT scan. Skeletal survey: E/N. Management: The patient underwent exenteration (right side).
	View Full Size Image
Media type:  Photo

Media file 3:  Patient with retinoblastoma, glaucomatous stage. Intracranial extension on CT scan.
	View Full Size Image
Media type:  CT

Media file 4:  Patient with retinoblastoma, glaucomatous stage. Another CT scan slice, showing the intracranial extension of the tumor.
	View Full Size Image
Media type:  CT

Media file 5:  Retinoblastoma, extraocular stage (neglected with necrosis). History: RC, 2-year-old male with chief complaint of left orbital mass. Born full term spontaneous vaginal delivery (FTSVD) to a gravida 3, para 2 (2001) at home. Three months prior to admission (PTA), an inward deviation of the left eye was noted. No consultation. Six months PTA, opacity in the left eye was noted. Five months PTA, proptosis of the left eye with pain and bleeding was noted. Family/Social History: Indigent family. Youngest of 3 siblings; eldest sibling had no retinoblastoma; second sibling had retinoblastoma and underwent enucleation, dying after 2 sessions of chemotherapy. A cousin passed away with retinoblastoma. Examination: Indirect ophthalmoscopy of right eye revealed a large intraocular mass occupying the inferior half of the retina. Mass on left side. Management: The patient was scheduled for exenteration, left side. The mother and child went home against medical advice; what happened to the patient is not known.
	View Full Size Image
Media type:  Photo

Media file 6:  Status post (S/P) enucleation for retinoblastoma, right eye retinoblastoma, recurrence, right eye. History: IJ, 3-year-old male with chief complaint of right orbital mass. At age 2 months, opacity in right eye is noted. Five months prior to admission (PTA), consultation with an ophthalmologist for proptosis, right eye. Four months PTA, the patient underwent enucleation, right eye, with no alleged tumor involvement of the tumor resection margins on histopathology. One month PTA, gradually enlarging orbital mass, right side, was noted. Examination: Visual acuity right eye, not applicable (S/P enucleation); visual acuity left eye, at least 6/12 (20/40). No masses are seen in left eye on indirect ophthalmoscopy. Diagnostics: Skeletal survey showed lytic lesions on the humerus, femur, and pubic bones.
	View Full Size Image
Media type:  Photo

Media file 7:  Retinoblastoma, intraocular stage (CT scan findings). History: 5-month-old female with chief complaint of "cat's eye reflex." Two months prior to admission (PTA), cat's eye reflex noted with outward deviation of left eye. The patient's 29-year-old mother had bilateral retinoblastoma and underwent enucleation, left eye, at age 2 years. Examination: Regressed type stage III, left eye visual acuity (+) dazzle right eye; indirect ophthalmoscopy (+) mass nasal retina with seeding, multiple tumors in peripheral retina, left eye. E/N Retina: Right eye. Management: The patient underwent enucleation, left eye. Examination under anesthesia of right eye: E/N. Histopathology: Retinoblastoma, intraocular stage, well-differentiated left eye.
	View Full Size Image
Media type:  CT

Media file 8:  Classic histologic finding of retinoblastoma (Flexner-Wintersteiner rosettes)
	View Full Size Image
Media type:  Image

Media file 9:  Flexner-Wintersteiner rosettes in retinoblastoma
	View Full Size Image
Media type:  Image

Media file 10:  Presenting signs or symptoms in retinoblastoma. (This table is modified from Abramson DH, Frank CM, Susman M, et al: Presenting signs of retinoblastoma. J Pediatr 1998 Mar; 132(3 Pt 1): 505-8.)
	View Full Size Image
Media type:  Image

Media file 11:  Reese-Ellsworth classification of retinoblastoma
	View Full Size Image
Media type:  Image

Media file 12:  Classic regression patterns of retinoblastoma
	View Full Size Image
Media type:  Image

Media file 13:  Genetic counseling for retinoblastoma. (This table is modified from Vogel F: Genetics of retinoblastoma. Hum Genet 1979; 52:1.)
	View Full Size Image
Media type:  Image

Media file 14:  Vitreous seeding (intraocular retinoblastoma). Courtesy of Manolette Roque, MD, Ophthalmic Consultants Philippines Co, EYE REPUBLIC Ophthalmology Clinic.
	View Full Size Image
Media type:  Photo

Media file 15:  Reese-Ellsworth Stage V: vitreous seeding. Courtesy of Manolette Roque, MD, Ophthalmic Consultants Philippines Co, EYE REPUBLIC Ophthalmology Clinic.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Abramson DH, Frank CM, Susman M, et al. Presenting signs of retinoblastoma. J Pediatr. Mar 1998;132(3 Pt 1):505-8. [Medline].
• Abranson DH. Second nonocular cancers in retinoblastoma: a unified hypothesis. The Franceschetti Lecture. Ophthalmic Genet. Sep 1999;20(3):193-204. [Medline].
• Albert DM. Historic review of retinoblastoma. Ophthalmology. Jun 1987;94(6):654-62. [Medline].
• Apushkin MA, Apushkin MA, Shapiro MJ. Retinoblastoma and simulating lesions: role of imaging. Neuroimaging Clin N Am. Feb 2005;15(1):49-67. [Medline].
• Badhu B, Sah SP, Thakur SK. Clinical presentation of retinoblastoma in Eastern Nepal. Clin Experiment Ophthalmol. Aug 2005;33(4):386-9. [Medline].
• Beck MN, Balmer A, Dessing C, et al. First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol. Aug 2000;18(15):2881-7. [Medline].
• Biswas J, Mani B, Shanmugam MP, et al. Retinoblastoma in adults. Report of three cases and review of the literature. Surv Ophthalmol. Mar-Apr 2000;44(5):409-14. [Medline].
• Bunin GR, Petrakova A, Meadows AT, et al. Occupations of parents of children with retinoblastoma: a report from the Children''s Cancer Study Group. Cancer Res. Nov 15 1990;50(22):7129-33. [Medline].
• Chan HS, Gallie BL, Munier FL. Chemotherapy for retinoblastoma. Ophthalmol Clin North Am. Mar 2005;18(1):55-63, viii. [Medline].
• Chantada GL, de Davila MT, Fandino A, et al. Retinoblastoma with low risk for extraocular relapse. Ophthalmic Genet. Sep 1999;20(3):133-40. [Medline].
• Cowell JK. The genetics of retinoblastoma. Br J Cancer. Mar 1991;63(3):333-6. [Medline].
• DiCiommo D, Gallie BL, Bremner R. Retinoblastoma: the disease, gene and protein provide critical leads to understand cancer. Semin Cancer Biol. Aug 2000;10(4):255-69. [Medline].
• Dudgeon J. Retinoblastoma--trends in conservative management. Br J Ophthalmol. Feb 1995;79(2):104. [Medline].
• Dudgeon J. Unilateral retinoblastoma--genetic implications. Br J Ophthalmol. Mar 1996;80(3):193. [Medline].
• Ferris FL 3rd, Chew EY. A new era for the treatment of retinoblastoma. Arch Ophthalmol. Nov 1996;114(11):1412. [Medline].
• Finger PT, Czechonska G, Demirci H, Rausen A. Chemotherapy for retinoblastoma: a current topic. Drugs. Dec 1999;58(6):983-96. [Medline].
• Friedman DL, Himelstein B, Shields CL, et al. Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol. Jan 2000;18(1):12-7. [Medline].
• Gombos DS, Diba R. Estimating the incidence of retinoblastoma in Texas. Tex Med. Jul 2005;101(7):70-2. [Medline].
• Hamel P, Budning AS, Heon E, Gallie BL. Focal therapy in the management of retinoblastoma: when to start and when to stop. J AAPOS. Dec 2000;4(6):334-7. [Medline].
• Harbour JW. Overview of RB gene mutations in patients with retinoblastoma. Implications for clinical genetic screening. Ophthalmology. Aug 1998;105(8):1442-7. [Medline].
• Harini R, Ata-ur-Rasheed M, Shanmugam MP. Genetic profile of 81 retinoblastoma patients from a referral hospital in southern India. Indian J Ophthalmol. Mar 2001;49(1):37-42. [Medline].
• Heimann H, Bechrakis NE, Zepeda LC. Exposure of orbital implants wrapped with polyester-urethane after enucleation for advanced retinoblastoma. Ophthal Plast Reconstr Surg. Mar 2005;21(2):123-8. [Medline].
• Honavar SG, Singh AD. Management of advanced retinoblastoma. Ophthalmol Clin North Am. Mar 2005;18(1):65-73, viii. [Medline].
• Hungerford J. Factors influencing metastasis in retinoblastoma. Br J Ophthalmol. Sep 1993;77(9):541. [Medline].
• Joseph B, Shanmugam MP, Srinivasan MK. Retinoblastoma: genetic testing versus conventional clinical screening in India. Mol Diagn. 2004;8(4):237-43. [Medline].
• Journee-de Korver HG, Midena E, Singh AD. Infrared thermotherapy: from laboratory to clinic. Ophthalmol Clin North Am. Mar 2005;18(1):99-110, viii-ix. [Medline].
• Kaelin WG. Functions of the retinoblastoma protein. Bioessays. Nov 1999;21(11):950-8. [Medline].
• Kao LY, Yang ML. Spontaneous regression of retinoblastoma in a Taiwan series. J Pediatr Ophthalmol Strabismus. Jul-Aug 2005;42(4):228-32. [Medline].
• Khan AO, Al-Mesfer S. Lack of efficacy of dilated screening for retinoblastoma. J Pediatr Ophthalmol Strabismus. Jul-Aug 2005;42(4):205-10; quiz 233-4. [Medline].
• Kim NJ, Choung HK, Khwarg SI. Free orbital fat graft to prevent porous polyethylene orbital implant exposure in patients with retinoblastoma. Ophthal Plast Reconstr Surg. Jul 2005;21(4):253-8. [Medline].
• Kingston JE, Hungerford JL, Madreperla SA, Plowman PN. Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol. Nov 1996;114(11):1339-43. [Medline].
• Kivela T. Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol. Jun 1999;17(6):1829-37. [Medline].
• Lee CT, Bilton SD, Famiglietti RM. Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques?. Int J Radiat Oncol Biol Phys. Oct 1 2005;63(2):362-72. [Medline].
• Linn Murphree A. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am. Mar 2005;18(1):41-53, viii. [Medline].
• Lipinski MM, Jacks T. The retinoblastoma gene family in differentiation and development. Oncogene. Dec 20 1999;18(55):7873-82. [Medline].
• Lohmann DR. RB1 gene mutations in retinoblastoma. Hum Mutat. 1999;14(4):283-8. [Medline].
• MacDonald DJ, Lessick M. Hereditary cancers in children and ethical and psychosocial implications. J Pediatr Nurs. Aug 2000;15(4):217-25. [Medline].
• Margo C, Hidayat A, Kopelman J, Zimmerman LE. Retinocytoma. A benign variant of retinoblastoma. Arch Ophthalmol. Oct 1983;101(10):1519-31. [Medline].
• Mashayekhi A, Shields CL, Eagle RC. Cavitary changes in retinoblastoma: relationship to chemoresistance. Ophthalmology. Jun 2005;112(6):1145-50. [Medline].
• Matsubara H, Makimoto A, Higa T. A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant. Apr 2005;35(8):763-6. [Medline].
• Mietz H, Hutton WL, Font RL. Unilateral retinoblastoma in an adult: report of a case and review of the literature. Ophthalmology. Jan 1997;104(1):43-7. [Medline].
• Miller DM, Murray TG, Cicciarelli NL. Pars plana lensectomy and intraocular lens implantation in pediatric radiation-induced cataracts in retinoblastoma. Ophthalmology. Sep 2005;112(9):1620-4. [Medline].
• Mittnacht S. The retinoblastoma protein--from bench to bedside. Eur J Cell Biol. Mar 2005;84(2-3):97-107. [Medline].
• Moll AC, Imhof SM, Meeteren AY, Boers M. At what age could screening for familial retinoblastoma be stopped? A register based study 1945-98. Br J Ophthalmol. Oct 2000;84(10):1170-2. [Medline].
• Nork TM, Millecchia LL, de Venecia GB, et al. Immunocytochemical features of retinoblastoma in an adult. Arch Ophthalmol. Nov 1996;114(11):1402-6. [Medline].
• O''Doherty M, Lanigan B, Breathnach F. A retrospective review of visual outcome and complications in the treatment of retinoblastoma. Ir Med J. Jan 2005;98(1):17-20. [Medline].
• Pendergrass TW, Davis S. Incidence of retinoblastoma in the United States. Arch Ophthalmol. Jul 1980;98(7):1204-10. [Medline].
• Pochanugool L, Hathirat P, Kunavisarut S, Pairachvet V. Radiation treatment of retinoblastoma: experience in the past two decades. J Med Assoc Thai. Jun 1994;77(6):308-13. [Medline].
• Schuler A, Weber S, Neuhauser M. Age at diagnosis of isolated unilateral retinoblastoma does not distinguish patients with and without a constitutional RB1 gene mutation but is influenced by a parent-of-origin effect. Eur J Cancer. Mar 2005;41(5):735-40. [Medline].
• Schvartzman E, Chantada G, Fandino A, et al. Results of a stage-based protocol for the treatment of retinoblastoma. J Clin Oncol. May 1996;14(5):1532-6. [Medline].
• Shanmugam MP, Biswas J, Gopal L. The clinical spectrum and treatment outcome of retinoblastoma in Indian children. J Pediatr Ophthalmol Strabismus. Mar-Apr 2005;42(2):75-81; quiz 112-3. [Medline].
• Shields CL, Shields JA, Needle M, et al. Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma. Ophthalmology. Dec 1997;104(12):2101-11. [Medline].
• Shields CL, Shields JA, Meadows AT. Chemoreduction for retinoblastoma may prevent trilateral retinoblastoma. J Clin Oncol. Jan 2000;18(1):236-7. [Medline].
• Shields CL, De Potter P, Himelstein BP, et al. Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol. Nov 1996;114(11):1330-8. [Medline].
• Shields CL, Mashayekhi A, Cater J. Macular retinoblastoma managed with chemoreduction: analysis of tumor control with or without adjuvant thermotherapy in 68 tumors. Arch Ophthalmol. Jun 2005;123(6):765-73. [Medline].
• Shields CL, Materin MA, Shields JA. Review of optical coherence tomography for intraocular tumors. Curr Opin Ophthalmol. Jun 2005;16(3):141-54. [Medline].
• Shields CL, Mashayekhi A, Cater J. Chemoreduction for retinoblastoma: analysis of tumor control and risks for recurrence in 457 tumors. Trans Am Ophthalmol Soc. 2004;102:35-44; discussion 44-5. [Medline]</