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 (Flexner-Wintersteiner 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 18,000-30,000 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).
o 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.

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.
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.
Sources 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
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: 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.
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, 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 related
studies.
[13]

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.
[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)
o 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]

o 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.
o 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.



DD
1. Katarak congenital
A cataract is an opacification of the lens. Congenital cataracts usually are diagnosed at birth. If a cataract
goes undetected in an infant, permanent visual loss may ensue. Not all cataracts are visually significant. If a
lenticular opacity is in the visual axis, it is considered visually significant and may lead to blindness. If the
cataract is small, in the anterior portion of the lens, or in the periphery, no visual loss may be present.
Unilateral cataracts are usually isolated sporadic incidents. They can be associated with ocular
abnormalities (eg, posterior lenticonus, persistent hyperplastic primary vitreous, anterior segment
dysgenesis, posterior pole tumors), trauma, or intrauterine infection, particularly rubella.
Bilateral cataracts are often inherited and associated with other diseases. They require a full metabolic,
infectious, systemic, and genetic workup. The common causes are hypoglycemia, trisomy (eg, Down,
Edward, and Patau syndromes), myotonic dystrophy, infectious diseases (eg, toxoplasmosis, rubella,
cytomegalovirus, and herpes simplex [TORCH]), and prematurity.
2.






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.
View full drug information
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.
View full drug information
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.
View full drug information
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.
Immunosuppressants
Class Summary
The addition of cyclosporine in combination with chemotherapy regimen of carboplatin, etoposide, and vincristine
reportedly have showed enhanced efficacy of chemotherapy.
View full drug information
Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated 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.


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 (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 theJournal 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.