RETINOBLASTOMA
PRESENTER: KYOMUHENDO MICHELLE
SUPERVISOR : DR. KAYINA
DEFINITION
• Retinoblastoma is an embryonal malignancy of the retina and the
most common intraocular tumor in children.
• The survival rate of children with retinoblastoma in developed
countries is extremely high, while it progresses to metastatic disease
and death in >40% of children in low income countries.
• The associated loss of vision and side effects of therapy are significant
problems that remain to be addressed
EPIDEMIOLOGY
• The cumulative lifetime incidence of retinoblastoma is approximately 1 in
20,000 live births.
• It accounts for 2% of all pediatric malignancies.
• The Median age at diagnosis is approximately 2 years, >90% of cases are
diagnosed in children and >90% of cases are diagnosed in children < 5
years.
• 66–75% of children with retinoblastoma have unilateral tumors, with the
remainder having bilateral retinoblastoma, which is more common in
younger children, diagnosed before age 1 year, and is always heritable.
• Risk of retinoblastoma may be increased in children conceived by in vitro
fertilization.
ETIOLOGY
• Retinoblastoma can be either be hereditary or sporadic.
HEREDITARY
• Usually diagnosed at a younger age, are multifocal and bilateral.
SPORADIC OR NON HEREDITARY
• Usually diagnosed in older children who tend to have unilateral,
unifocal involvement.
ETIOLOGY
• The hereditary form is associated with loss of function of the retinoblastoma gene
(RB1) via a pathogenic variant or deletion.
• RB1 is located on chromosome 13q14 and encodes the retinoblastoma protein, a
tumor suppressor protein that controls cell cycle phase transition and has roles in
apoptosis and cell differentiation.
• Children with 13q deletion syndrome are at increased risk to develop
retinoblastoma.
• Many causative pathogenic variants have been identified, including
translocations, deletions, insertions, point pathogenic variants, and epigenetic
modifications such as gene methylation.
• The nature of the predisposing pathogenic variant can affect the penetrance and
expressivity of retinoblastoma development.
PATHOGENESIS
ALFRED KNUDSON’S 2 HIT HYPOTHESIS.
• According to the 2 hit hypothesis, two pathogenic variant events are
required for retinoblastoma tumor development.
• In the hereditary form of retinoblastoma, the first pathogenic variant
in RB1 is inherited through germinal cells, and a pathogenic variant
occurs subsequently in somatic retinal cells.
• In the sporadic form of retinoblastoma, the two pathogenic variants
occur in somatic retinal cells.
• Heterozygous carriers of oncogenic RB1 pathogenic variants
demonstrate variable phenotypic expression.
PATHOGENESIS
• Histologically, retinoblastoma appears as a small, round blue cell
tumor with rosette formation (Flexner-Wintersteiner rosettes).
• It may arise in any of the nucleated layers of the retina and exhibit
various degrees of differentiation.
• Retinoblastoma tumors tend to outgrow their blood supply, resulting
in necrosis and calcification.
PATHOGENESIS
• Endophytic tumors arise from the inner surface of the retina and grow
into the vitreous and can also grow as tumors suspended within the
vitreous itself, known as vitreous seeding.
• . Exophytic tumors grow from the outer retinal layer and can cause
retinal detachment.
• Tumors can also be both endophytic and exophytic.
• These tumors can also spread by direct extension to the choroid or
along the optic nerve beyond the lamina cribrosa to the central
nervous system, or by hematogenous or lymphatic spread to distant
sites, including bones, bone marrow, and lungs.
Illustration of the lamina
cribrosa
CLINICAL MANIFESTATION
• Leukocoria, a white pupillary reflex, which often is first noticed when
a red reflex is not present at a routine newborn or well-child
examination or in a flash photograph of the child.
• Strabismus often is an initial presenting complaint.
• Decreased vision
• orbital inflammation
• Hyphema i.e bleeding in the eye.
• pupil irregularity can occur with advancing disease.
• Pain can occur if secondary glaucoma is present.
Strabismus
Orbital inflammation
hyphema
RETINOBLASTOMA STAGING
• The International Intraocular Retinoblastoma Classification groups
retinoblastomas into five stages based on the extent of the cancer and the
chances of saving the eye.
• Stage 0; tumor is in the eye and treated without surgery.
• Stage I; tumor is in the eye and eye has been removed with no remaining
cancer cells.
• Stage II; tumor is in the eye and eye has been removed but there are
microscopic cancer cells.
• Stage III The cancer has spread from the eye to nearby tissues or lymph nodes.
• Stage IV The cancer has spread to other parts of the body, such as the bone,
liver, brain, or spinal cord.
DIAGNOSIS
• Ophthalmologic findings of a chalky, white-gray retinal mass with a
soft, friable consistency.
• Imaging studies are not diagnostic, and biopsies are contraindicated.
• Indirect ophthalmoscopy with slit-lamp evaluation can detect
retinoblastoma tumors, but a complete evaluation requires an
examination under general anesthesia by an experienced
ophthalmologist to obtain complete visualization of both eyes, which
also facilitates photographing and mapping of the tumors.
• Retinal detachment or vitreous hemorrhage can complicate the
evaluation.
Indirect ophthalmoscopy with slit-lamp examination under general
evaluation anesthesia
DIAGNOSIS
• Orbital ultrasonography, CT, or MRI is used to evaluate the extent of
intraocular disease and extraocular spread.
• In approximately 5% of cases, a pineal area (primitive neuroectodermal)
tumor is detected in a child with hereditary and bilateral retinoblastoma,
a phenomenon known as trilateral retinoblastoma.
• MRI allows for better evaluation of optic nerve involvement. Metastatic
disease is rarely present at diagnosis
• Cerebrospinal fluid and bone marrow evaluation for tumor metastasis
and radionuclide bone scan are required only if indicated by other
clinical, laboratory, or imaging findings.
DIFFERENTIALS
These include other causes of leukocoria like;
• persistent hyperplastic primary vitreous
• Coats disease
• vitreous haemorrhage
• cataract
• endophthalmitis from Toxocara canis
• choroidal coloboma
• retinopathy of prematurity
• familial exudative vitreoretinopathy
SCREENING
• Children with a positive family history of retinoblastoma should
undergo a dilated eye examination under general anesthesia early in
life and at regular intervals until genetic testing is performed and
results are available.
• Infants with a negative genetic test require no further screening;
infants with a positive genetic test require regular screening
ophthalmologic examinations until age 7 years.
• Only about 10% of retinoblastoma cases are detected by routine
ophthalmologic screening in the context of a positive family history.
TREATMENT
• Treatment is determined by the size and location of the tumors, if the
disease is localized to the eye or has spread either to the brain or to
the rest of the body, and whether the child has hereditary or sporadic
disease.
• The primary goal of treatment is always cure.
• The secondary goals include preserving vision and the eye itself and
decreasing the risk of late side effects, mainly secondary
malignancies.
TREATMENT
• Enucleation is performed if useful vision cannot be salvaged.
• Enucleation may also be required for unresponsive or recurrent
tumors.
• With bilateral disease, chemoreduction in combination with focal
therapy (laser photocoagulation or cryotherapy) has replaced the
traditional approach of enucleation of the more severely affected eye
and irradiation of the remaining eye.
• If feasible, small tumors can be treated with focal therapy with careful
follow-up for recurrence or new tumor growth.
TREATMENT
• Larger tumors often respond to multiagent chemotherapy, including
carboplatin, vincristine, and etoposide given intravenously.
• However, systemic therapy is generally reserved for patients with
unilateral disease when high-risk features are noted after enucleation,
or in very young patients with bilateral disease that are at higher risk
of complications with intraarterial chemotherapy.
• The delivery of chemotherapy via the ophthalmic artery is becoming
more common, as is delivery of intravitreal chemotherapy.
TREATMENT
• If these approaches fail, external-beam irradiation should be
considered, although this approach may result in significant orbital
deformity and increased incidence of second malignancies in patients
with germline RB1 pathologic genetic variants.
• Brachytherapy, or episcleral plaque radiotherapy, is an alternative
with less morbidity.
• Intense multiagent chemotherapy with autologous stem cell rescue
may be used for patients with metastatic disease.
PROGNOSIS
• Current efforts using chemotherapy in combination with focal
therapy are intended to preserve useful vision and avoid external-
beam radiation or enucleation.
• Unfortunately, the diagnosis of retinoblastoma in many children from
resource-poor countries is delayed, resulting in spread of the tumor
outside the orbit.
• The prognosis for children with retinoblastoma that has spread
outside the eye is poor.
• Trilateral retinoblastoma, disease involving both eyes and the pineal
region, is almost universally fatal.
PROGNOSIS
• Children with germline RB1 pathologic genetic variants are at
significant risk for development of second malignancies, especially
osteosarcoma, as well as soft tissue sarcomas and malignant
melanoma.
• The risk of second malignancies is further increased by the use of
radiation therapy.
• Other radiation-related late adverse effects include cataracts, orbital
growth deformities, lacrimal dysfunction, and late retinal vascular
injury.
REFERENCES
• Nelson Textbook of Paediatrics, 21th Edition, vol. 1, Elsevier,
Philadelphia
