Retinoblastoma for undergraduate MBBS Students. Covers the basics of Aetiology, Genetics, pathophysiology, clinical features, Classification and management of Retinoblastoma. Also encompasses salient points for PGMEE

1. RETINOBLASTOMA
Dr. Abhishek Onkar

2. • Primary malignant neoplasm of the retina that arises from immature
retinal cells
• It is the most common primary intraocular malignancy of childhood

3. INHERITANCE
• 60–70% of retinoblastoma – unilateral
• 30–40% are bilateral.
• In unilateral cases, only a single tumor is usually present in the
affected eye.
• In bilateral cases, multifocal tumors in both eyes are the rule.
• Retinoblastoma is generally a sporadic condition (i.e., no previously
affected family members exist)
• Approximately 6% of newly diagnosed retinoblastoma cases are
familial and 94% are sporadic.
• Sporadic form of retinoblastoma are affected unilaterally.
• Familial cases have a autosomal dominant inheritance.

4. Classification
• Unifocal/multifocal.
• Unilateral (70%) or bilateral (30%).
• Sporadic (94%) or familial (6%).
• Non hereditary (50-60%) or hereditary (40-50%).
• It is recognized that bilateral and familial retinoblastoma are caused
by a germline mutation and are thus a heritable tumor.

5. • Bilateral retinoblastomas involve germinal mutations in all cases.
• Approximately 15% of unilateral sporadic retinoblastoma is caused by
germinal mutations affecting only one eye while the 85% are
sporadic.
• Knudson two-hit hypothesis
• The retinoblastoma gene (RB1) is located on the long arm of
chromosome 13 (13q14).
• Overexpression of MYCN (2p)

6. Histopathology of Retinoblastoma
• On low magnification, basophilic areas of tumor are seen along with
eosinophilic areas of necrosis and more basophilic areas of calcification
within the tumor.
• Poorly differentiated tumors consist of small to medium sized round cells
with large hyperchromatic nuclei and scanty cytoplasm with mitotic
figures.
• Well-differentiated tumors show the presence of rosettes and fleurettes.
• These can be of various types.:
• Flexner-Wintersteiner rosettes consist of columnar cells arranged around a
central lumen. This is highly characteristic of retinoblastoma and is also
seen in medulloepithelioma.

7. • Homer Wright rosettes consist of cells arranged around a central
neuromuscular tangle. This is also found in neuroblastomas,
medulloblastomas and medulloepitheliomas.
• Pseudorosette refers to the arrangement of tumor cells around blood
vessels. They are not signs of good differentiation.
• Fleurettes are eosinophilic structures composed of tumor cells with
pear shaped eosinophilic processes projecting through a fenestrated
membrane.
• Rosettes and fleurettes indicate that the tumor cells show
photoreceptor differentiation.

8. Life-Threatening Problems
Children with retinoblastoma are at risk for three important,
• life-threatening problems including metastasis from retinoblastoma,
• intracranial neuroblastic malignancy (trilateral retinoblastoma), and
• second primary tumors.

9. At Risk for Metastasis
• Retinoblastoma metastasis, when it occurs, generally develops within 1
year of the diagnosis of the intraocular tumor.
• Those at greatest risk for metastasis show features of:
1. retinoblastoma invasion beyond the lamina cribrosa in the optic nerve,
2. in the choroid (>2 mm dimension),
3. sclera,
4. Orbit
5. anterior chamber.
• Eyes with invasion of the optic nerve or choroid generally demonstrate
large retinoblastoma over 15 mm greatest dimension along with elevated
intraocular pressure and total retinal detachment.

10. At Risk for Neuroblastic Intracranial Malignancy
(Trilateral Retinoblastoma)
• There is an association of neuroblastic intracranial malignancy in
patients with the hereditary form of retinoblastoma, most often
manifesting as pineoblastoma.

11. At Risk for Second Primary Tumors
• child with retinoblastoma has approximately a 5% chance of
developing another malignancy during the first 10 years of follow-up,
18% during the first 20 years, and 26% within 30 years.
• Osteogenic sarcoma, often involving the femur, is most common
• other tumors such as spindle cell sarcoma, chondrosarcoma,
rhabdomyosarcoma, neuroblastoma, glioma, leukemia, sebaceous
cell carcinoma, squamous cell carcinoma, and malignant melanoma
have also been recognized.
• The mean latency period for the appearance of the second primary is
approximately 13 years.

12. Clinical Features of Retinoblastoma
• The clinical manifestations of retinoblastoma vary with the stage of the
disease at the time of recognition.
• In its earliest clinical stage, a small retinoblastoma, ie, less than 2 mm in
basal dimension, appears ophthalmoscopically as a subtle, transparent or
slightly translucent lesion in the sensory retina.
• Slightly larger tumors lead to dilated retinal blood vessels that feed and
drain the tumor.
• Some larger tumors show foci of chalk-like calcification that resemble
cottage cheese.
• Any retinoblastoma of any size can produce leukocoria (visible whiteness in
the pupil/ amaurotic "cat's eye reflex")

13. • Leucocoria is the most common presenting feature of retinoblastoma, followed by
strabismus, painful blind eye and loss of vision.
Common presenting features of retinoblastoma as reported in studies:
• 1. Leucocoria 56%
• 2. Strabismus 20%
• 3. Red painful eye 7%
• 4. Poor vision 5%
• 5. Asymptomatic 3%
• 6. Orbital cellulitis 3%
• 7. Unilateral mydriasis 2%
• 8. Heterochromia iridis 1%
• 9. Hyphema 1%

17. • As the tumor grows further, three patterns are usually seen
1. Endophytic, in which the tumor grows into the vitreous cavity. A yellow
white mass progressively fills the entire vitreous cavity and vitreous
seeds occur. The retinal vessels are not seen on the tumor surface.
2. Exophytic, in which the tumor grows towards the subretinal space.
Retinal detachment usually occurs and retinal vessels are seen over the
tumor
3. Diffuse infiltrating tumor, in which the tumor diffusely involves the retina
causing just a placoid thickness of the retina and not a mass. This is
generally seen in older children and usually there is a delay in the
diagnosis

21. Classification of Retinoblastoma
• Several classifications of retinoblastoma have been developed to
assist in prediction of globe salvage. The most popular grouping is the
Reese-Ellsworth classification
• A new International Classification of Retinoblastoma is currently being
developed to simplify the grouping scheme and allow a more
practical approach to judging results of chemoreduction.

22. Reese-Ellsworth Classification for
Conservative Treatment of Retinoblastoma*
Group I: Very favorable
• (a) Solitary tumor, less than 4 disc diameters in size, at or
• behind the equator
• (b) Multiple tumors, none over 4 disc diameters in size, all at
• or behind the equator
Group II: Favorable
• (a) Solitary tumor, 4 to 10 disc diameters in size, at or
• behind the equator
• (b) Multiple tumors, 4 to 10 disc diameters in size,
• behind the equator

23. Group III: Doubtful
• (a) Any lesion anterior to the equator
• (b) Solitary tumors larger than 10 disc diameters
• behind the equator
Group IV: Unfavorable
• (a) Multiple tumors, some larger than 10 disc diameters
• (b) Any lesion extending anteriorly to the ora serrata
Group V: Very unfavorable
• (a) Massive tumors involving over half the retina
• (b) Vitreous seeding
* Refers to chances of salvaging the affected eye and not systemic prognosis.

24. Differential Diagnosis
• The most common pseudoretinoblastomas include persistent
hyperplastic primary vitreous, Coats’ disease, and ocular toxocariasis

25. Conditions Closely Simulating Retinoblastoma
• Persistent hyperplastic primary vitreous 28
• Coats’ disease (exudative retinitis or retinal telangiectasis) 16
• Ocular toxocariasis 16
• Retinopathy of prematurity 5
• Combined hamartoma 4
• Coloboma 4
• Vitreous hemorrhage 4
• Astrocytic hamartoma 3
• Congenital cataract 2
• Toxoplasmic retinitis 1
• Idiopathic endophthalmitis 1

26. Diagnostic Testing
• Accurate diagnosis in a child with suspected retinoblastoma is
accomplished by taking a detailed history, physical evaluation, external
ocular examination, slit lamp biomicroscopy, and binocular indirect
ophthalmoscopy with scleral indentation.
• The diagnosis is established by the classic appearance of the retinal tumors
• Needle biopsy confirmation is rarely, if ever, necessary.
• Ancillary diagnostic studies can be helpful in confirming the diagnosis of
retinoblastoma.
• Fluorescein angiography shows early vascularity and late
hyperfluorescence of the tumor.

27. • Ultrasonography and computed tomography can demonstrate the
intraocular tumor and possibly detect calcium within the mass.
• Approximately 5% to 10% of retinoblastomas show no intrinsic
calcification
• Magnetic resonance imaging does not usually detect calcium but may
be of value in the assessment of the optic nerve, orbit, and brain.

28. Diagnosis of Retinoblastoma

29. Other Classifications of Retinoblastoma
International Classification of Intraocular Retinoblastoma
(Murphree)
International Classification of Retinoblastoma (Shields)
TNM Classification for Retinoblastoma
Pathologic Classification (pTNM)

30. International Staging System for Retinoblastoma
Stage 0 No enucleation (one or both eyes may have intraocular disease)
Stage I Enucleation, tumor completely resected
Stage II Enucleation with microscopic residual tumor
Stage III Regional extension
• A. Overt orbital disease
• B. Preauricular or cervical lymph node extension
Stage IV Metastatic disease
• A. Hematogenous metastasis
• 1. Single lesion
• 2. Multiple lesions
• B. CNS Extension
• 1. Prechiasmatic lesion
• 2. CNS mass
• 3. Leptomeningeal disease

31. Management of Retinoblastoma
• The most important objective in the management of a child with
retinoblastoma is survival of the patient, and the second most
important goal is preservation of the globe.
• The focus on visual acuity comes later, after safety of the patient and
globe is established.
• Therapy is tailored to each individual case and based on the overall
situation, including threat of metastatic disease, risks for second
cancers, systemic status, laterality of the disease, size and location.

32. Current Suggested Protocol
A. Intraocular tumor, International Classification Group A to C, Unilateral or Bilateral
1. Focal therapy (cryotherapy or transpupillary thermotherapy) alone for smaller
tumors (< 3mm in diameter and height) located in visually noncrucial areas
2. Standard 6 cycle chemoreduction and sequential aggressive focal therapy for
larger tumors and those located in visually crucial areas
3. Defer focal therapy until 6 cycles for tumors located in the macular and
juxtapapillary areas. Transpupillary thermotherapy or plaque brachytherapy for
residual tumor in the macular and juxtapapillary areas >6 cycles.
4. Focal therapy for small residual tumor, and plaque brachytherapy/external
beam radiotherapy (>12 months age) for large residual tumorif bilateral, and
enucleation if unilateral.

33. B. Intraocular tumor, International Classification Group D, Unilateral or
Bilateral
1. High dose chemotherapy and sequential aggressive focal therapy
2. Periocular carboplatin for vitreous seeds
3. Consider primary enucleation if unilateral, specially in eyes with no
visual prognosis

34. Intraocular tumor, International Classification Group E, Unilateral or Bilateral
1. Primary enucleation
2. Evaluate histopathology for high risk factors
• D. High risk factors on histopathology, International Staging, Stage 2
• 1. Baseline systemic evaluation for metastasis
• 2. Standard 6 cycle adjuvant chemotherapy
• 3. High dose adjuvant chemotherapy and orbital external beam
• radiotherapy in patients with scleral infiltration, extraocular extension, and
optic nerve extension to transection.

35. E. Extraocular tumor, International Staging, Stage 3A
1. Baseline systemic evaluation for metastasis
2. High dose chemotherapy for 3-6 cycles, followed by enucleation or
extended enucleation, external beam radiotherapy, and continued high
dose chemotherapy for 12 cycles
F. Regional Lymph Node Metastasis, International Staging, Stage 3B
1. Baseline evaluation for systemic metastasis
2. Neck dissection, high dose chemotherapy for 6 cycles, followed by
external beam radiotherapy, and continued high dose chemotherapy
for 12 cycles

36. G. Hematogenous or Central Nervous System Metastasis, International
Staging, Stage 4
• 1. Palliative therapy in discussion with the family
• 2. High dose chemotherapy with bone marrow rescue for
hematogenous metastasis
• 3. High dose chemotherapy with intrathecal chemotherapy for central
nervous system metastasis

37. Chemoreduction Regimen for Intraocular Retinoblastoma
Given for a Total of 6 Monthly Cycles
• Day Vincristine Etoposide Carboplatin
• 0 × × ×
• 1 ×
• Vincristine: 0.05 mg/kg
• Etoposide: 5 mg/kg
• Carboplatin: 18.6 mg/kg

38. Focal Therapies
Focal therapies include laser photocoagulation, thermotherapy,
cryotherapy, and plaque radiotherapy.
Plaque radiotherapy is generally reserved for tumors that fail other
focal therapies, even those that reach a moderate size, up to 8 or 10
mm in thickness.
The remainder of the focal therapies are reserved for small tumors,
generally those under 3 mm in greatest dimension.

39. • Laser photocoagulation is usually employed for small retinoblastomas
posterior to the equator of the eye.
• Thermotherapy is a method of tumor heating using a diode infrared
laser system. Thermotherapy coupled with chemoreduction is
especially suited for tumors adjacent to the fovea and optic nerve
where radiation or laser photocoagulation would possibly induce
more visual loss
• Cryotherapy is useful in the treatment of equatorial and peripheral
small retinoblastomas.

40. • Plaque radiotherapy is a method of brachytherapy in which a
radioactive implant is placed on the sclera over the base of a
retinoblastoma to irradiate the tumor transsclerally.
• Generally, it is limited to tumors less than 16 mm in base and 8 mm in
thickness.
• It requires an average of 2 to 4 days of treatment time to deliver the
total dose of 40 Gy to the apex of the tumor.

42. External Beam Radiotherapy
• Retinoblastoma is generally a radiosensitive tumor. External beam
radiotherapy is a method of delivering whole eye irradiation to treat
advanced retinoblastoma, particularly when there is diffuse vitreous
seeding.

43. Enucleation
• Enucleation is a frequently used and important method for managing
retinoblastoma. If there is advanced disease with no hope for useful
vision in the affected eye or if there is a concern of invasion of the
tumor into the optic nerve, choroid, or orbit, then enucleation is
appropriate.
• Those eyes with secondary glaucoma, pars plana seeding, or anterior
chamber invasion are also generally best managed with enucleation.

44. Primary enucleation continues to be the treatment of choice for
• advanced intraocular retinoblastoma with neovascularization of iris,
• secondary glaucoma,
• anterior chamber tumor invasion,
• tumors occupying >75% of the vitreous volume,
• necrotic tumors with secondary orbital inflammation, and
• tumors associated with hyphema or vitreous hemorrhage where the
tumor characteristics can not be visualized, especially when only one
eye is involved

45. Special considerations for enucleation in retinoblastoma
• a. Minimal manipulation
• b. Avoid perforation of the eye
• c. Harvest long (> 15 mm) optic nerve stump
• d. Inspect the enucleated eye for macroscopic extraocular extension and
• optic nerve involvement
• e. Harvest fresh tissue for genetic studies
• f. Place a primary implant
• g. Avoid biointegrated implant if postoperative radiotherapy is necessary

47. Histopathologic high-risk factors predictive of metastasis
• • Anterior chamber seeding
• • Iris infiltration
• • Ciliary body infiltration
• • Massive choroidal infiltration
• • Invasion of the optic nerve lamina cribrosa
• • Retrolaminar optic nerve invasion
• • Invasion of optic nerve transection
• • Scleral infiltration
• • Extrascleral extension