Background

Retinoblastoma is the most common primary ocular malignancy (eye cancer) of childhood. Peter Pawius of Amsterdam provided the first description of a tumor resembling retinoblastoma. 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 as filled with a "substance similar to brain tissue mixed with thick blood and like crushed stone."[1] 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.[2] 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.[3] In 1836, Langenbech, Robin, and Nystin of Paris confirmed by microscopic studies that the tumor definitely arose from the retina. In 1864, Virchow named the tumor a glioma of the retina, supporting glial cells as the cell of origin of the tumor.[4] In 1891, Flexner of Johns Hopkins was first to notice rosettes within the tumor (shown in the image below).[5] 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.[6] Presently, their names are attached to these rosettes.

Classic histologic finding of retinoblastoma (FlexnerWintersteiner rosettes) Most cells comprising the tumor histologically resemble the cells of an undifferentiated retina of the embryo called retinoblasts. This resemblance prompted Verhoeff to coin the term retinoblastoma,[7] 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.[8, 9]

In October of 2007, a team of investigators at St. Jude Children's Research Hospital (Memphis, Tenn) claimed to have identified the specific cell that gives rise to retinoblastoma.[10] The major importance of this discovery is the idea that retinoblastoma can arise from fully matured nerves in the retina called horizontal interneurons, disproving the long-held scientific principle that fully formed, mature nerves cannot multiply like young immature cells.

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 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 is typically associated with vitreous seeding, wherein small fragments of tissue become separated from the main tumor. In some instances, vitreous seeding may be extensive and allow 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 is often 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 retinoblastomas. 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.

Epidemiology

Frequency United States

An estimated 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 18,00030,000 live births, depending on the country. In the Philippines, unpublished reports have estimated the incidence to be more 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, these figures 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 rates for 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.
Race

No racial predilection appears to exist for retinoblastoma. No difference in incidence exists among blacks and whites.

Sex

Studies show no significant difference in the incidence of retinoblastoma by sex for children aged 0-14 years. The estimated boy-to-girl ratio is reportedly 1.12:1.

Age

Retinoblastoma is diagnosed in patients at an average of 18 months, with 90% of cases diagnosed in patients younger than 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.

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 in any of the family members. Only about 5% of patients who develop this disease have a positive family history. 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. The image below presents an overview of the presenting signs in retinoblastoma.

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.)

Leukocoria (white pupillary reflex or cat's eye reflex) is the most common presenting sign, accounting for about 56.1% of cases. Leukocoria is shown in the image below.

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. 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. o Pseudouveitis, with a red eye and pain and 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. o Orbital inflammation mimicking orbital cellulitis may occur in eyes with necrotic tumors and does not necessarily imply extraocular extension. o The glaucomatous stage is shown in the image below.

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). The extraocular stage is shown in the image below.

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. 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 the gene 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. Castera et al identified MDM2 as the first modifier gene for retinoblastoma.[11] MDM2 increases p53 and pRB catabolism, both of which are involved in the development of retinoblastoma. A study of 326 individuals in 70 retinoblastoma families found that MDM2 is strongly associated with bilateral and unilateral retinoblastoma development.

Differential Diagnoses

Cataract, Congenital Hemorrhage, Vitreous Retinal Detachment, Exudative Retinopathy of Prematurity Tuberculosis Uveitis, Anterior, Childhood

Laboratory 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. o 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. o Sources of DNA to be evaluated directly are either from tumor cells or leukocytes. o Deletions or rearrangements of the retinoblastoma gene can be detected by either karyotyping or Southern blotting techniques. o 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. o 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. o 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
Computed tomography

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 (examples shown below). This neuroimaging technique is also invaluable in assessing the CNS anatomy, including the optic nerve, for possible extension of retinoblastoma.

Patient with retinoblastoma, glaucomatous stage. Intracranial

extension on CT scan. Patient with retinoblastoma, glaucomatous stage. Another CT scan slice, showing the intracranial extension of the tumor.

Retinoblastoma, intraocular stage (CT scan findings). History: 5month-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. Ultrasonography

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. Certain ADC values calculated at T3-weighted imaging are correlated with some of the accepted parameters of poor prognosis for retinoblastoma, particularly degree of differentiation of the tumor and tumor size.[12]
X-ray studies

In areas of the world where ultrasonography and computerized tomography are not available, xray studies may be the only means of identifying intraocular calcium in patients with opaque media.

Other Tests

Immunohistopathologic staining o 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. o 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. o 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. o 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 related studies.[13] o Bridges and colleagues performed biochemical assays and showed interphotoreceptor retinoid-binding protein (IRBP) in retinoblastoma. These findings suggested an embryonic origin of the cells. o 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. o Complete eye examination should be performed including an estimation of the patient's visual acuity for both eyes. o 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 o 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). o 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.[14]

Histologic Findings
The classic histologic findings of retinoblastoma are Flexner-Wintersteiner rosettes (shown in the image below) and less commonly fleurettes.

Flexner-Wintersteiner rosettes in retinoblastoma A Homer-Wright rosette can be encountered, but they are also 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 is

usually 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 therapy (EBRT) 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 the image below.

Reese-Ellsworth classification of retinoblastoma

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

External beam radiation therapy o Incidence of local control is high and retinal late effects are minimal with radiation doses of 4000-4500 cGy used with 200 cGy fractions. However, morbidity and mortality associated with external beam radiation therapy (EBRT) are significant. EBRT results in cessation of bone growth. Therefore, children with retinoblastoma who are treated with EBRT have significant midface hypoplasia. (The younger the child is when EBRT is instituted, the more dramatic the outcome.) More importantly, EBRT has been 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 (The best method of treatment is being debated in such a case.) Radioactive isotope plaques o Use of radioactive 60 Co (cobalt); radioactive 125 I (iodine), which is presently the most used; radioactive 192 Ir (iridium); or 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. o Advantage - Locally directed treatment to the tumor, minimizing radiation to the normal tissue o Disadvantage - Incomplete treatment, high dose to local sclera, significantly less irradiation for anterior lesions, and difficulty placing posterior plaques Chemotherapy o 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. o Prophylactic chemotherapy is recommended if a tumor is in the optic nerve past the lamina cribrosa because these cases have a poor survival prognosis. o Use of neoadjuvant chemotherapy has the advantage of limiting the necessity for EBRT and reducing the possibility of EBRT-related complications. o 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.[15] o 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.[16] o 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. o 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. o Abramson and colleagues have demonstrated successful salvage of eyes typically enucleated for advanced disease.[17] Intra-arterial chemotherapy for advanced retinoblastoma offers another weapon in the arsenal of therapies for retinoblastoma. However, there are still potential complications to consider, and, consequently, this procedure should be performed at tertiary care institutions that specialize in the care of patients with retinoblastoma. Novel therapy o A study by Yi Qu et al used immunohistochemical analysis of normal retina and retinoblastoma tumor specimens acquired from multiple centers in order to evaluate the pathological associations of the nuclear factor-B (NF-B) subunits and retinoblastoma. The data point to the fact that therapeutic strategies targeting

NF-B together with other therapies may represent a novel approach to retinoblastoma therapy.[18] Suzuki et al conducted a study with selective arterial injection involving a balloon catheter and melphalan. It achieved a success rate of 98.8% and had few severe adverse events, including secondary neoplasms. The rate of preservation was more than half for treated eyes, and more than half of the eyes without macular tumors maintained a visual acuity of more than 0.5. No severe eye damage or severe systemic events were detected; secondary neoplasms were observed but no more frequently than otherwise expected.[19]

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

Enucleation o Enucleation is performed when there is no chance of preserving useful vision in an eye. o 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. o Significant orbital growth retardation remains after enucleation for retinoblastoma.[20] The younger the patient is at the time of surgery, the more growth retardation occurs. Cryotherapy o 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. o 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. o 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 o Photocoagulation can be used as primary therapy for small posteriorly located tumors. o There is a danger of producing large field defects near the disc and decreased vision resulting from macular pucker by photocoagulation near the macula. o The technique is performed by placing a double row of confluent burns around each tumor using a photocoagulator. o 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. o Successful treatment with photocoagulation takes weeks to evolve and consists of complete disappearance of the tumor, which is replaced with a flat area.

Photocoagulation can also be used for tumor recurrences after EBRT. Exenteration is still performed, especially in most underdeveloped countries, when extension of the tumor into the surrounding areas is considerable.

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.

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

Anticancer drugs

Class Summary

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

vincristine (Rx) - Oncovin, Vincasar PFS

Class: Antineoplastics, Vinca Alkaloid

Vincristine (Vincasar, Oncovin PFS)

Cycle-specific and phase-specific, which blocks mitosis in metaphase. Binds to microtubular protein, tubulin, GTP dependent. Blocks ability of tubulin to polymerize to form microtubules, which leads to rapid cytotoxic effects and cell destruction.

Dosing & Uses

AdultPediatric Dosing Forms & Strengths Acute Leukemia

1.4 mg/m IV qWeek

Combination Therapy

Cancers

Hodgkin's Disease, Non Hodgkin's Malignant Lymphomas, Rhabdomyosarcoma, Neuroblastoma, and Wilm's Tumor Consult dose modifications in multi-drug regimens

Uveal Melanoma (Orphan)

Indicated for metastatic uveal melanoma Orphan indication sponsor

Hana Biosciences, Inc; 7000 Shoreline Court; Suite 370; South San Francisco, CA 94080

Renal Impairment

Dose adjustment not necessary

Hepatic Impairment

Decrease dose 50% if direct bilirubin >3 mg/dL [51 umol/L] Monitor: CBC
Other Indications & Uses

ALL, AML, CML, Hodgkin's disease, NHL, neuroblastoma, sarcomas, small cell lung cancer, Wilms' tumor, brain tumors Off-label: breast cancer, idiopathic thrombocytopenic purpura, Kaposi's sarcoma, bladder cancer
Carboplatin (Paraplatin)

Inhibits both DNA and RNA synthesis. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of the cell cycle, but cell is most vulnerable to action of these drugs in G1 and S phase.
Dosing Forms & Strengths Advanced Ovarian Carcinoma

Single agent: 360 mg/m IV q4Weeks Combination treatment: 300 mg/m IV (plus cyclophosphamide 600 mg/m IV) q4Weeks
Dose Modifications

For SI units: Count in US units x 10^6/L Give full dose if

Platelets 50-100,000 Neutrophils 500-2000

Give 125% if

Platelets >100000 Neutrophils >2000

Give 75% if

Platelets <50000 Neutrophils <500

Renal Impairment

CrCl 41-59 mL/min: 250 mg/m IV on day 1 CrCl 16-40 mL/min: 200 mg/m IV on day 1 CrCl <15 mL/min: Not recommended
Hepatic Impairment

Dose adjustment may not be necessary; not studied

Administration

Do not repeat dose until ANC >2000 AND platelets >100000 Infuse over >15 minutes Monitor: CBC weekly
Other Indications & Uses

Off-label: testicular cancer, head and neck cancer, cervix cancer, small cell lung cancer, progressive diffuse large B-cell lymphoma
Etoposide (Toposar, VePesid)

Blocks cells in the late S-G2 phase of the cell cycle. Binding of drugs to enzyme-DNA complex results in persistence of transient cleavable form of complex and, thus, renders it susceptible to irreversible double strand breaks.
Dosing Forms & Strengths Testicular Cancer

50-100 mg/sq.meter/d IV on days 1-5, OR 100 mg/sq.meter/d IV on days 1, 3, 5 Repeat q3-4week

Small-Cell Lung Cancer

35 mg/sq.meter/d IV x 4 d, OR

50 mg/sq.meter/d IV x 5 d; repeat q3-4week

Monitor

CBC, Hgb, LFTs, renal function

Other Information

Equivalent IV doses for etoposide & etoposide phosphate PO: 2 x IV dose, rounded to nearest 50 mg
Other Indications & Uses

Off-label: Hodgkin's disease, non-Hodgkin's lymphoma (NHL), leukemias, Kaposi's sarcoma, Wilms tumor, bone marrow transplantation, many other neoplasias

Immunosuppressants
Class Summary

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

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cellmediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease for a variety of organs. For children and adults, base dosing on ideal body weight.
Dosing Forms & Strengths Solid Organ Transplantation

Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants; has been used in combination with azathioprine and corticosteroids Adjust dosage according to trough levels, general dosage guidelines listed below Oral

4-12 hours pre-transplant: 15 mg/kg PO for 1 dose 1-2 weeks post-transplant: 15 mg/kg/day PO divided BID

Reduce 5% per week until: 5-10 mg/kg/day PO divided BID

IV

4-12 hours pre-transplant IV: 5-6 mg/kg IV for 1 dose over 2-6 hours Post-transplant, until can tolerate oral therapy: 5-6 mg/kg IV qDay

Rheumatoid Arthritis

Indicated for severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate; may be used in combination with methotrexate Gengraf or Neoral: 1.25 mg/kg PO BID; may increase by 0.5-0.75 mg/kg/day after 8 weeks and again after 12 weeks if needed, not to exceed 4 mg/kg/day Discontinue if no improvement observed by 16 weeks Decrease dose by 25-50% at any time to control adverse effects (eg, hypertension, elevations in serum creatine >30% pretreatment level
Psoriasis

Indicated for treatment of adult, nonimmunocompromised patients with severe, recalcitrant, plaque psoriasis who have failed to respond to at least 1 systemic therapy (eg, PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated Gengraf or Neoral: 1.25 mg/kg PO BID; may increase by 0.5 mg/kg/day after 4 weeks and q2wk if needed, not to exceed 4 mg/kg/day Discontinue if no improvement observed at 6 weeks on maximum daily dose of 4 mg/kg/day Decrease dose by 25-50% at any time to control adverse effects (eg, hypertension, elevations in serum creatine >30% pretreatment level
Orphan Indications

ALS

Treatment of amyotropohic lateral sclerosis and its variants Orphan indication sponsor: Maas Biolab,LLC; Tecnology Ventures, Corporation Technopolis 1155 University Blvd., SE; Albuquerque, NM 87106

Traumatic Brain Injury

Treatment of moderate-to-severe traumatic brain injury

Orphan indication sponsor: NeuroVive Pharmaceutical AB, Biomedical Center SE-221 84; Lund, Sweden

Lung Transplant

Prophylaxis of organ rejection in patients receiving allogeneic lung transplant Treatment of acute rejection in recipients of allogeneic lung transplants Orphan indication sponsor: APT Pharmaceuticals, Inc; 700 Airport Blvd, Suite 350; Burlingame, CA 94010

GVHD

Prophylaxis and treatment of graft versus host disease Orphan indication sponsor: Sigmoid Pharma LTD; Dublin City University; Ireland

Lung Allograft Rejection

Liposomal: For aerosolized administration in the prevention and treatment of lung allograft rejection Orphan indication sponsor: Vernon Knight, M.D.; Baylor College of Medicine, Dept. of Molecular Phy, One Baylor Plaza; Houston, TX 77030

Pulmonary Rejection With BMT

Liposomal: For aerosolized administration in the prevention and treatment of pulmonary rejection events associated with bone marrow transplant (BMT) Orphan indication sponsor: Vernon Knight, M.D.; Baylor College of Medicine, Dept. of Molecular Phy, One Baylor Plaza; Houston, TX 77030

Bronchioitis Obliterans (Orphan)

Liposomal cyclosporine for inhalation Orphan indication sponsor: PARI Pharma GmbH; Moosstrasse 3; Germany

Administration

Neoral and Sandimmune are NOT bioequivalent, exercise caution if switching between brands/generics

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 monitored indefinitely. Patients and siblings of patients in whom the risk of retinoblastoma cannot be ruled out by genetic studies should be monitored 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 thereafter. 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. Visual acuity, alignment, and general ocular health should be should be periodically examined in office. 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 the image below. Classic regression patterns of retinoblastoma As long as the tumor is not enlarging, it can be considered to be locally controlled by radiation therapy.

Inpatient & Outpatient Medications

Only supportive medications during chemotherapy or after surgery are needed. These include antinausea 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, they are as follows: 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 (ReeseEllsworth 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, as shown below. 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 use of molecular genetics techniques, although this sometimes can prove to be very

expensive. Genetic counseling for retinoblastoma. (This table is modified from Vogel F. Genetics of retinoblastoma. Hum Genet 1979; 52:1.) Normal individuals have 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.