Retinoblastoma in Pediatric Hematology and Oncology ward

1. Presenters:
Dr. ReneshaIslam
Dr. FarzanaAlamMou
Resident (Phase B)
Pediatric Hematology and Oncology
Bangabandhu Sheikh Mujib Medical University
WELCOME
TO
SEMINAR

2. Case scenario 1 Case scenario 1

4. Outlines
• Anatomy of eye & retina
• History
• Introduction
• Epidemiology
• Classification
• Genetics
• Pathology
• Clinical presentation
• Differential diagnosis
• Staging
• Grouping
• Investigations
• Treatment
• Recurrent retinoblastoma
• Follow-up
• Genetic counseling
• Prognosis

5. Anatomy of Eye

6. Anatomy of Retina

7. History
o Peter Pawius of Amsterdam provided the description of
a tumor resembling RB. He described as “Substance
similar to brain tissue mixed with thick blood and like
crushed stone” in 1597.
o In 1809, James Wardrop, a scottish surgeon 1st
recognized that retinoblastoma is a discrete tumor
arising from retina based on gross pathological findings.
o In 1864, Virchow, thought that the cell of origin was glial
and named it ‘glioma of retina’.

8. History
oIn the late 1800s, Flexner and Wintersteiner proposed
the term neuroepithelioma, because they believed that
the tumor originated from the neuroepithelium.
oEarly 1900s, Verhoef concluded that the tumor was
derived from undifferentiated embryonic retinal cells
called retinoblast and proposed the term retinoblastoma.
o The American ophthalmological society first
adopted the term retinoblastoma in 1926.

9. oRetinoblastoma is a malignant tumor of the embryonic
retina.
oMost common intraocular malignancy in children.
3% of all childhood cancers.
oAlthough usually not recognized at birth, retinoblastoma
predominantly affects young children.
oThe tumor has a variable growth rate, can originate from
single or multiple foci in one or both eyes & in bilateral
cases, may be manifest in one eye many months before it
is evident in the other.
Introduction

10. oCaused by a mutation in a gene that expresses a protein
central to the control of the cell cycle and may occur
sporadically or be inherited.
oChildren with the hereditary type of retinoblastoma
have a particular susceptibility to developing other
malignant tumors.
Introduction

11. o Incidence: 11 per million under 5 years of
age or 1 in 20,000 live births.
oThere are no racial or gender predilection.
o Most common in India and Africa.
o11% of cancers developing in the first year
of life, but for only 3% of all cancers younger
than 15 years of life.
oAbout 80% of cases are diagnosed before 3
to 4 years of life.
Epidemiology
10.1200/jgo.18.22400 Journal of Global Oncology 4, no. Supplement 2

12. Epidemiology
o 90% of cases : under 3 years of age.
o Extremely low by 6 years of age.
o 60–70% of retinoblastoma – Unilateral.
o 30–40% - Bilateral.
o In Pediatric hematology & oncology department of
BSMMU (2017-2020) – 3 patient (2 female, 1 male).
Meanageatdiagnosis
Familyhistory 4 months
Bilateraldisease 12 months
Unilateraldisease 24 months
AAO BCSC 2015: Ophthalmic pathology and intraocular tumors - Retinoblastoma

15.  On The Basis Of Laterality:
oUnilateral tumors:
-One or more tumors in one eye.
-Median age of presentation-23 months.
-May be synchronous or metachronous.
-For unifocal cases it may be nonhereditary & for
multifocal cases it may be hereditary with younger age
of presentation.
Classification

16. oBilateral tumors:
-One or more tumors in both eyes.
-Can be synchronous or metachronous.
-It is presumed that these patients have the hereditary
form of the disease, even in the form of positive family
history.
-Age of presentation-before 2 yrs & most present in the
1st year of life.
oTrilateral tumors:
-Bilateral hereditary retinoblastoma with
neuroectodermal pineal tumor (pineoblastoma).
-Usually occurs below 5 years of age.
Classification

17. On The Basis Of Focality:
oUnifocal:
-Most likely to be nonhereditary.
oMultifocal:
-Most likely to harbor a germline mutation in the RB1
gene.
Classification

18.  On the basis of heredity:
oHereditary retinoblastoma:
-40% (15%-unilateral, 25%-bilateral)
-Presence of germline mutation.
-Mutations in the RB1 gene appear to be inherited as
an autosomal dominant pattern.
-Earlier clinical manifestation of disease with disease
detectable in utero in children with known familial
disease.
-Very elevated risk of developing secondary
malignancies.
Classification

19. -All children with bilateral tumors
and roughly 15% of children with
unilateral tumors have this form
of disease.
-85% of these are new
spontaneous mutations
(sporadic), while the remaining
have a positive family history
(familial).
-Risk of developing second
malignancy is 6%.
-Risk increases 5-fold if exposed
to radiation.
Classification

20. oNonhereditary retinoblastoma: 60%
-Inherit two normal copies of RB1
gene.
-Post conception two somatic
mutations occur, one in each copy
of the RB1 gene in a retinoblast &
tumor results.
-Usually unifocal or unilateral
tumors.
-Risk of siblings is 1%.

21. oFamiliar retinoblastoma: 10%
-Inherited from an affected parent or unaffected carrier
parent.
-Mutation in RB1 gene present in all cases including the
germline.
-Generally multifocal and bilateral.
-Risk of secondary non ocular malignancy.
oSporadic retinoblastoma: 90%
-Sporadic bilateral-30%, sporadic unilateral-60%)
-Typically present with unilateral unifocal disease at latter
stage.
-Bilateral cases has been associated with advanced
paternal age.
On the basis of family history

23. oIntraoccular:
-With endophytic growth, there is a white hazy mass.
-With exophytic growth, there is retinal detachment.
-Most tumors have combined growth.
-Retinal cells frequently break off from the main mass
and seed the vitreous, or new locations on the retina.
-Glaucoma may result from occlusion of the trabecular
network or from iris neovascularization.
On the basis of pattern of spread

24. oExtraoccular :
-RB spreads first to soft tissues surrounding the eye or
invades the optic nerve. From there it can spread
directly along the axons to the brain, or may cross into
the subarachnoid space and spread via the CSF to the
brain.
-Hematogenous spread leads to metastatic disease,
most commonly to brain, lungs, bone marrow, or
bone.
RB can spread lymphatically to the preauricular and
submandibular nodes.

25. oEndophytic:
-Tumors arising from the retina
& growing into the vitreous cavity.
-The tumors tend to entirely fill the
cavity & produce floating tumor
spheres called vitreous seeds.
-If left untreated eventually invades
the anterior portion of the eye, reaching
the acquous venous channels and the
conjunctiva, then through lymphatic channels
metastasize to regional lymph nodes.
On the basis of growth pattern:

26. o Exophytic:
- Grow from the retina into the subretinal space.
- Often cause serious detachments of the retina.

27. o Mixed :
-Most common pattern.

28. oDiffuse infiltrating:
-Least common.
-Most diagnostically challenging.
-No predominant mass.
-the tumor cells grow throughout the retina while
single cells and vitreous seeds
invade the anterior portions of
retina, the cilliary body, and
anterior chamber.
-clinically presents as
pseudohypopyon, uveitis.
-Tumor diffusely involves retina
causing placoid thickness of retina (not mass).

29. Genetics

30. RB1 Gene
oRB occurs as a result of mutations
of RB1 gene located on long arm of
chromosome 13 (13q14).
oThis was the first tumor suppressor
gene cloned.

32. ALFRED KNUDSON’S TWO HIT HYPOTHESIS (1971)

33. Gross features:
--Tumors are usually white-gray with a chalky appearance
and a soft friable consistency. Bright white speckles
corresponding to calcifications are present throughout the
tumor.
--The gross features depend mainly on the growth pattern.
Pathology

34. Growth Patterns
o Endophytic:
- White to cream-colored mass breaks through internal
limiting membrane.
- No surface vessels or small, irregular tumor vessels.
- Associated with vitreous seeding.
Endophytic tumour with vitreous seeding

35. Growth Patterns
o Exophytic:
- Yellow-white lesion in subretinal space.
- Overlying retinal vessels increased in caliber and tortuosity.
- Associated subretinal fluid and RD that can obscure the
tumour.
May be difficult to visualize
through deep detachment
Exophytic tumour

36. Growth Patterns
o Diffuse infiltrating:
- Flat infiltration of retina without discrete tumormass.
- Conjunctival chemosis, pseudohypopion,vitritis.
-Large tumor can be both endophytic and exophytic.
Intraretinal tumour
whole eye section shows a mixed endophytic
(into the vitreous) and exophytic (into the
subretinal space) growth pattern

37. oComposed of small basophilic cells(retinoblasts) with
large hyperchromatic nuclei (round, oval or spindle-
shaped) and scanty cytoplasm.
oHigh mitotic activity.
oMany retinoblastomas are
undifferentiated but varying
degree of differentiation,
characterised by formation of
Rosettes.
Histology
Undifferentiated tumour

38. 1) Flexner -Wintersteiner rosettes:
consists of central lumen
surrounded by tall columnar cells,
nuclei of which lie away from the
lumen.
2) Homer-Wright rosettes (pseudo-
rosettes) : (Less common)
It has no lumen & cells. Form around a
tangled mass of eosinophilic processes .
Also found in other neuroblastic tumor.
3)Fleurettes:
cluster of cells with long cytoplasmic
processes, projecting through a
fenestrating membrane & appearance
resembles the bouquet of flowers.

39. The signs and symptoms of intraoccular tumor depend on its size & position.
Clinical presentations
Leukocoria -56% Strabismus -20% Secondary glaucoma-1%
Hyphema—1% Orbital inflammation-3% Orbital invasion-1%

40. .
Clinical presentations
H
Red eye – 7% Pseudohypopyon -1%
Heterochromia-1% Massive Proptosis-1%

41. ASSOCIATED PRIMARY MALIGNANCIES
Leukemia
Neuroblastoma
Chondrosarcoma
Osteosarcoma
Rhabdomyosarcoma 13

42. Multiple congenital anomalies associated with
retinoblastoma -0.5%
Congenital cardiovascular defects.
Cleft palate.
Infantile cortical hyperostosis.
Dentinogenesis imperfecta.
Familial congenital cataracts.
Incontinentia pigmenti.
.

43. Differential Diagnosis
• Cataract
• Retinopathy of prematurity
• Coats’ disease
• Persistent fetal vasculature
• Toxocariasis
• Cellulitis
• Metastasis
• Coloboma
• Herpes simplex retinitis
• Cytomegalovirus retinitis
• Toxoplasmosis
• Norrie’s disease
• Astrocytic hamartoma
• Retinal detachment
• Combined hamartoma of the retinal
pigment epithelium
• Myelinated nerve fiber

44. International staging system for retinoblastoma:
Stage-0: Patients treated conservatively.
Stage-I: Eye enucleated, completely resected histologically.
Stage-II: Eye enucleated, 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: (b)CNS extension:
1.Single lesion 1.Prechiasmatic lesion
2.Multiple lesions. 2.CNS mass
3.Leptomeningeal disease.
Staging

45. Flow chart showing Routes of Spread

46. Investigations in Retinoblastoma

47. Plan of investigation
DIAGNOSIS FOR TREATMENT PURPO
SE
METASTASIS EVALUA
TION
Evaluation under
anesthesia
Retinal cam
Genetic study
RB gene if availa
ble
IMAGING
• MRI/ CT SCA
N Brain and
Orbit
 CBC
 SGPT
 S. Creatinine
 S. Electrolyte
 S. magnesium,
 S. Calcium
 CcR
 Audiology
 MRI Brain
 Chest Xray
 CT Chest
 Bone marrow a
spiration
( pancytopenia)
 Bone scan
( Bone pain)
 CSF study

48. 1. Examination of eye Under Anesthesia (EUA):
• Most important test for retinoblastoma.
• Should be done by an expert ophthalmologi
st:
–After appropriate sedation, and
–Pupillary dilatation.

49. – Diagnostic finding of retinoblastoma :
• A Creamy-white or snow-white mass
• Projecting from retina into the vitreous.

50. Differential diagnoses

51. Congenital
cataract
Retinopathy of
prematurity
Coat’s disease
Toxocara canis
infection
Persistent
hyperplastic primary
vitreous
Retinal detachment

52. Classification of Intra-ocular RB (International Classification of RB
- ICRB):
• It is based on the ophthalmoscopic findings: 5 groups (A to E)
Group A
(Small retinal tumors):
• Small (<3mm)
retinal tumor,
• At least 3 mm
away from fovea/disk.
Group A retinoblastoma
(multi-focal)
Normal fundus

53. Group B Retinoblastoma
(Large retinal tumors):
• All other retinal tumors
– >3 mm in size
– Near fovea/disk

54. Group C Retinoblastoma:
(Focal seeds)
– Focal (<3 mm from tumor)
– Vitreous or/&
– Sub-retinal seeds

55. Group D Retinoblastoma:
(Diffuse seeds)
– Diffuse (>3 mm from tumor)
– Vitreous or/&
– Sub-retinal seeds

56. • Group E Retinoblastoma
(Extensive retinoblastoma):
– >50% globe occupied,
– Neovascular glaucoma,
– Buphthalmos.

57. Other Investigations for extra-ocular
tumor
• CT scan/ MRI of brain and orbit:
Extent of tumor in orbit,
Optic nerve involvement (ONI),
Pineoblastoma in Tri-lateral RB,
CNS metastasis.

58. – CSF for malignant cells
– MRI spine (if focal neurologic signs)
– Bone scan (if bone pain)
– Bone marrow study (if cytopenias).

59. • Base line organ functions:
– CBC,
– Liver and renal function,
– Serum calcium, magnesium and electrolytes
– Baseline hearing assessment

60. – Pathologic confirmation:
– Is not required for starting treatment of Retinoblastoma .
– In diagnostic dilemma, FNAB (Fine needle aspiration biopsy) may be done
To exclude-
• Atypical uveitis,
• Endophthalmitis,
• Non-visualized retina due to-
– Cataract /
– Hemorrhage in anterior/posterior chamber.
– Better to avoid to prevent iatrogenic dissemination.
Pseudo-rossettes in retino-
blastoma

61. • Histopathology:
– In advanced retinoblastoma, surgical enucleation is done.
– Samples for hispathology are:
• Entire eye ball and
• Optic nerve ( atleast 10 mm).
– Macroscopically:
• Chalky, friable mass, necrotic areas.

62. Microscopic histopathology
– Poorly differentiated:
– Some differentiation:
– Differentiated with fleurettes 
– Retinocytomas
Flexner-wintersteiner rossettes
(usually found)
Homer-write rosettes
(less common)

63. • Histopathology: Extent of disease
– Features of high risk of metastasis:
• Involvement of
– Optic nerve (Post-laminar),
– Choroid > 3 mm,
– Sclera,
– Anterior chamber.
– Microscopic residual disease:
• Involvement at
– cut surface of eyeball,
– cut end of optic nerve.

64. • Genetic testing:
– Mutation of RB1 gene: (if available)
• Germ line mutation of RB1 gene is assumed in
– Bilateral tumors, early onset tumors
– Positive family history.
• Unilateral tumors:
– Most (80%) have mutation in tumor alone (somati
c).
– 20% may have mutation in both tumor and blood (
germ line).

65. Treatment

66. Therapeutic modalities include the following
a combined multi modality approach
Paediatrics
Oncologist
Ophthalmologist
Radiation
Oncologist

67. • Counselling:
– It is a malignant disease.
– The primary goal is to save life.
– To save vision is a secondary objective.
– Early intervention is a must to save vision.
– In advanced disease, Enucleation is life saving.

68. • Treatment is complex and individualized.
• It depends on:
– Size and site of tumor,
– Extent of tumor (intra and extra ocular),
– Bilateral involvement
– Visual potential,
– Age of the patient.

69. • Mode of treatment are:
– Chemotherapy: Neo-adjuvant/ adjuvant
– Surgery (enucleation)
– Radiotherapy
• External beam RT
• Intensity Modulated RT
• Proton beam RT

70. –local ophthalmic therapy:
• Laser photocoagulation,
• Cryotherapy
• Thermotherapy
• Local chemotherapy (sub-tenon/ intra-vitreal/ intra-ar
terial carboplatin)
• Focal plaque radiotherapy (brachytherapy)

71. • Management of unilateral Group A Retinoblastoma:
• Focal therapy alone
– (Posterior tumor- laser, anterior tumor- cryotherapy)
– 2-4 cycles at 3-4 weeks interval.
Follow up
• Most tumors regress into a flat calcified scar.
• If progressive
disease
Chemotherap
y 
Radiotherapy

72. – Group B Retinoblastoma:
• Chemotherapy: 2 drugs
– Vincristine- 0.05 mg/kg - D1
– Carboplatin- 18.6 mg/kg- D1 2-6 cycles.
• Focal therapy:
– After 2 cycles of chemotherapy.
– 2-4 cycles.
F/U
• If progressive disease, Radiotherapy.

73. Group C Retinoblastoma:
– Chemotherapy: 3 drugs
• Vincristine- 0.05mg/kg, D1
• Carboplatin-14 mg/kg, D1,2 6 cycles
• Etoposide-6 mg/kg, D1,2
• G-CSF
– Local therapy
• Laser/cryo
• ± sub-tenon carboplatin
• F/U
– IF Progressive disease plaque radiotherapy EBRT

74. Group D/E (Extensive Retinoblastoma)
– Optic nerve/ CSF not involved
• Surgical Eneucleation,
• Histopathology
• Optic nerve/ CSF involved
• Neoadjuvant
chemotherapy: 2-3 cycles
• Surgical Eneucleation
• Plus
No microscopic
residue:
Adjuvant
chemotherapy
• If progressive
disease
• Microscopic residual
disease
• Adjuvant
chemotherapy
• Plus
• Radiotherapy

75. • Orbit involved:
– Intensive neo-adjuvant chemotherapy:
• Vincristine
• Carboplatin,
• Etoposide, 2-3 cycles
• Cyclophosphamide
• Doxorubicin
– Eneucleation
– Adjuvant chemotherapy : 4-6 cycles
– Radiotherapy

76. Metastatic retinoblastoma
Conventional treatment:
Newer approach
3 drug chemotherapy: 6-18months High dose chemotherapy
Vincristine Induction: 4 cycles: VCR,CIS, CYCLO,ETO
Carboplatin Consolidation: carbo, etop,thiotepa
Etoposide
Autologous stem cell rescue

77. Bilateral Retinoblastoma:
– Treatment depends on:
• Stage of the worse eye and
• Visual potential of the better eye
Worse eye-E
Better eye- A/B
Worse eye- C/D
Better eye- A/B
Both eyes- C-E Both eyes- A/B
Enucleation of wors
e eye,
Focal + chemo for b
etter eye.
3 agent chemo
+ Focal therapy
± EBRT (worse eye)
3 agent chemother
apy
+ focal therapy
2 agent chemother
apy
+ focal therapy
(conservative approach)

78. • Recurrent retinoblastoma:
– Small intraocular tumor:
– Focal therapy ( Cryo/thermo therapy ± focal che
motherapy or brachytherapy)
– Large intra-ocular tumor:
– Enucleation + External beam radiotherapy
– Extra-ocular recurrence:
• High dose chemotherapy+ Stem cell rescue+ Extern
al beam radiotherapy

79. Newer treatment

80. • Local chemotherapy:
– Sub-conjunctival/ intravitreal/ intra-arterial chemotherapy:
• Carboplatin
• Topotecan

81. • Suicide gene therapy:
Retinoblasto
ma
Defective adenovirus
which contains
Thymidine kinase
gene
Healthy retina
survives

82. Prognosis

83. • Prognosis:
– Survival rates:
• Localized intra-ocular tumor (A/B/C): 80-95%
• Advanced intra-ocular tumor (D/E): 40-60%
– Optic nerve involved: 60%
– Surgical margin is positive: 40%
• Extra-ocular/ metastatic tumor:
– Conventionally <5%
– HDCT with ASCR 40%
• CNS recurrence is usually fatal.

84. Follow-up

85. Follow-up:
– For Recurrences:
• Unilateral RB:
If eye is preserved – bilateral EUA: If enucleated- bilateral local examina
tion:
Monthly - till no active tumor for 3 EU
A,
3 monthly- till 3 years of age,
6 monthly –
till the age of 10 years.
3 monthly- 2 years,
6 monthly- till 5 years of age,
Yearly- till 10 years of age.

87. • Bilateral RB:
– Above + MRI of brain- 6 monthly- till 5
years of age (for trilateral RB).
• Extra-ocular RB:
– Local and systemic examination + MRI
of brain and orbit + CBC and biochemis
try.

88. – For visual assessment:
• Refraction: Most of the patients require correction of refracti
ve errors,
• Protective glasses should be used by all.
– For Hearing loss:
• Hearing assessment – yearly
– For Myeloid neoplasm:
• CBC- 3 monthly for 3-5 years

89. PREVENTION

90. • Genetic counselling:
– Indication:
• Early onset,
• Bilateral, multifocal tumor,
• Positive family history, or
• Germ line RB1 mutation.

91. • Counselling should target:
– Siblings of patients, and both have 40%
chance of disease
– Offspring of the survivors.

92. • Prenatal test-
• Can be done to exclude the risk of retinoblastoma during first pr
egnancy and detect predisposition to second pregnancy
• Post natal -In these children: ophthalmologic exam:
– At birth,
– 4 monthly, till 4 years of age.

93. • Early detection is very important to save vision or life
• High index of suspicion is required by all primary care physicians.

94. If any parent complains of
something abnormal in the
eye of a child,
Urgent ophthalmologic
referral may save both
vision and life.

95. • Prenatal versus Postnatal Screening for Familial
Retinoblastoma
American Academy Of Ophthalmology
• Vol 123 ,issue 12. December 2016
When a parent had retinoblastoma, prenatal molecular diag
nosis with early-term delivery increased the likelihood of
infants born with no detectable tumors, better vision outco
mes, and less invasive therapy. Prenatal molecular diagnos
is facilitates anticipatory planning for both the child and fa
mily.

96. • Retinoblastoma: A Sixteen-Year Review of the Presentation, Tr
eatment, and Outcome from a Tertiary Care Institute in Northe
rn India
• Ocular Oncology and Pathology
Ocul Oncol Pathol 2018; 4: 23-32
The study included 467 patients. Retinoblastoma was bilateral in 15
. Intraocular disease was seen in 301 patients and extraocular in
166 patients. Out of the 347 who received treatment, primary tr
eatment was chemoreduction in 228 and enucleation in 117. Loc
al recurrence was seen in 20, metastasis in 2, and deaths in 13.Hi
stopathological high risk features were significantly less in the ey
es that received chemoreduction (5.0%) versus primary enucleat
ion (20.8%) (p < 0.0004), but there was no difference in the rate
of metastasis, recurrence, and death between the two groups

97. • Recent advances and challenges in the management of
retinoblastoma
• Year : 2017 | Volume : 65 | Issue : 2 | Page : 133-139
• Indian journal of Ophthlmology
• The treatment of retinoblastoma (Rb) has improved significantly i
n recent times. Worldwide, there is an increasing trend to use co
nservative treatment modalities that aim to preserve the globe a
s well as vision with minimum morbidity. Recently, the use of targ
eted delivery of chemotherapy to the eye in the form of selective
intra-arterial and intravitreal chemotherapy has shown promising
results. Radiotherapy is beneficial in selected cases, either in the
form of plaque brachytherapy or as external beam radiotherapy.