2. RETINOBLASTOMA
➤ Malignant neoplasm of the retina, thought to originate from the photoreceptor
layer (cone lineage)
➤ Most common primary intraocular malignancy in children and the second most
common intraocular malignancy in the world; after choroidal melanoma.
AAO BCSC 2015: Ophthalmic pathology and intraocular tumors - Retinoblastoma
3. EPIDEMIOLOGY
➤ 1 in 17,000 life births; mostly diagnosed
before the age of 3 yrs.
➤ No sexual predilection
➤ Most common in India and Africa
➤ Bilateral disease in 1/3 of cases
AAO BCSC 2015: Ophthalmic pathology and intraocular tumors - Retinoblastoma
Mean age at diagnosis
Family history 4 months
Bilateral disease 12 months
Unilateral disease 24 months
4. GENETICS
➤ Mutation in RB1 gene (misnomer: tumor suppressor gene).
➤ Chromosomal location: 13q14
➤ Kundeson’s two hit theory (1971): Both genes must be mutated for the disease to
manifest. Therefore it is a recessive trait, however:
“in pedigrees, the tumor appears to be dominant because so many retinoblasts are at
risk that the probability that at least one will get the required mutation to develop a
tumor is at least 90–95%. A person with the cancer predisposing syndrome
phenotype (RB1+/−
) will develop retinoblastoma with a 90–95% probability”
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
5. TERMINOLOGY
➤ The term “hereditary” means “having inherited status” and is correctly used to
describe a patient or family in which the germ line mutation was passed down
from a previous generation.
➤ A new sporadic bilateral case of retinoblastoma when neither parent has the RB1
mutation is more precisely referred to as “heritable”.
➤ A unilaterally affected child who has one parent with a known RB1 mutation is
clearly both heritable and hereditary but obviously not “bilateral.”
➤
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
6. INHERITANCE
➤ 95% sporadic
➤ If bilateral disease: 98%
germ-line mutation
➤ Overall disease
penetrance 90%,
however there are
mutations which result
in low penetrance.
BCSC 2015: Retina and Vitreous
reaction (PCR), karyotyping, fluorescent in situ hybridization (FISH), multiplex ligation-
dependent probe amplification (MLPA), and RNA analysis. There is approximately a 95%
chance of finding a new mutation if one exists.
Genetic counseling for retinoblastoma can be very complex (Fig 19-1). A bilateral
retinoblastoma survivor has a 45% chance of having an affected child, whereas a unilat-
eral survivor has a 7% chance ofha' ing an affected child. Normal parents of a child with
bilateral involvement have less than a 5% risk ofhaving another child with retinoblastoma.
If parent: has bi lateral has unilateral
retinoblastoma retinoblastoma is unaffected
Chance of 45% 55% 7%-15% 85%-93% <<1% 99%
offspring having affected unaffected affected unaffected affected unaffected
retinoblastoma
A j A j A jLaterality 85% 15% 0% 85% 15% 0% 33% 67% 0%
bilateral unilateral
j
bilateral uni lateral
j
bilateral unilateral
jj 1 j 1 j 1Focality 100% 96% 40'/0 0% 100% 96% 4% 0°/o 100% 15% 85% 0%
multi- multi- uni-
j
multi- multi- uni-
j
mu lti- multi- uni-
j
focal focal focal focal focal focal focal focal focal
Chance of next
j j j j J j J J jsibling having
retinoblastoma 45% 45°o 45% 45% 45% 45% 45% 7%- 5%* <1 °/o* <1 °/o* <1
15%
'If parent is a carrier, then
Figure 19-1 Genetic counsel ing for retinoblastoma . (Chart created by David H. Abramson, MD!
7. HISTORIC OVERVIEW OF THE HUNT FOR RB GENE
➤ 1960s deletion of the small arm (13q syndrome) or
micro-deletions in chromosome 13 was associated
with retinoblastoma.
➤ Genetic mapping improved in the 1970s and the
exact location of the deletion was 13q14.1
➤ In that region, Estrase D enzyme (with measurable
activity) gene proved to be useful in linkage
studies
➤ Later in the 1985, Estrase D enzyme gene was
cloned and the sequences of the adjacent DNA was
able to be identified leading to the exact mapping
of the RB gene.
Ryan
8. KUNDESON TWO HIT THEORY
➤ Landmark paper in 1971 by Alfred
Knudson
➤ “In the dominantly inherited form
of the disease, one mutation is
inherited via the germ line and the
second occurs in somatic cells. In
the nonhereditary form, both
mutations occur in somatic cells”.
➤ This paper served now as the basis
for cancer pathogenesis as many
oncogenes are recessive with loss of
function as the main cause.
Knudson AG. Mutation and Cancer: Statistical Study of Retinoblastoma. Proceedings of the National Academy of Sciences of the United States of
America. 1971;68(4):820-823.
tissue. In other words, one copy of the region around RB was
lost during tumorigenesis. In 1985, Cavenee et al. went a step
further by showing that, in heritable cases, the germ line copy
of 13q (carrying the mutant RB1) that was passed among affected
family members was always the one that was retained in the
tumor.22
The chromosomal mechanisms involved in reduction to
homozygosity on 13q14 are shown in Figure 128.1.
gation of nonhereditary patients in the same family. Hence, non-
heritable patients contain somatic or nongermline RB1 gene
mutations (i.e., present only in somatic cells of the retina) are
somatic mosaics. Hereditary patients carry germ line RB1 muta-
tions (i.e., present in virtually all cells in the body, both somatic
and germ line).
Molecular genetics of retinoblastoma
Because of the autosomal dominant inheritance pattern for reti-
noblastoma, the RB1 gene was assumed for many years to act in
a dominant fashion.14
A major paradigm shift in the genetic
understanding of retinoblastoma, and cancer in general, began
with an enigmatic paper published in 1971 by Alfred Knudson,
who proposed that retinoblastoma was caused by two muta-
tional events: “In the dominantly inherited form of the disease,
one mutation is inherited via the germ line and the second occurs
in somatic cells. In the nonhereditary form, both mutations occur
in somatic cells.”13
The major implication of this “two-hit theory”
was that the RB1 gene functions in a recessive manner at the
cellular level – an unprecedented suggestion at the time. Today,
it is known that many cancer-causing genes are recessive or
tumor suppressor genes.
The Knudson hypothesis languished for another decade due
to a lack of scientific methods for identifying the RB1 gene. An
early clue to the location of the RB1 gene was the recognition in
the 1960s that a portion of a group D chromosome (13, 14 and
15) was occasionally deleted in retinoblastoma. Shortly after the
Knudson paper, new chromosome banding techniques allowed
chromosome 13 to be identified as the target of deletions.15
The
smallest common deleted region was later mapped to chromo-
some 13q14.1 to q14.3.16
An enzyme with a measurable activity,
esterase D, had been mapped to chromosome 13, and proved to
be critical for linkage analysis in the era before recombinant DNA
Fig. 128.1 Chromosomal mechanisms of loss of heterozygosity (or
reduction to homozygosity) that cause the loss of the second RB gene
allele in retinoblastoma.
Retinoblast genotype
after first hit
(mutation or deletion)
Tumor cell
genotype after
second hit
Nondisjunction 13 loss(–)
(–)
rb-
rb-
rb-
rb-
rb-
rb-
rb-
rb-
rb-
rb- Rb+
rb- Nondisjunction and
reduplication
Mitotic recombination
13q14 deletion
Gene inaction
Mutation
9. RETINOBLASTOMA GENE
➤ Mapped to 13q14.1
➤ Interestingly, most new germ line
RB1 mutations are of paternal
origin, suggesting that the gene is
more susceptible to mutation
during spermatogenesis rather
than oogenesis.
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
TumorsoftheRe
TumorsoftheRetina,Choroid,andVitre
throughout the gene with mutational hotspots
tides.29,30
Less than 10% of retinoblastoma patie
tutional chromosome 13q abnormality (usuall
can be detected by karyotyping.31,32
Deletion
extensive can be associated with the 13q-syn
tures such as growth and mental retardation
phism, microcephaly, skeletal anomalies, an
abnormalities. About 15–20% of germinal m
the mRNA transcript from this gene was either missing or
abnormal in size in most retinoblastomas. Even though some
early workers questioned whether this gene was indeed RB1,27
further work has confirmed that this is the gene that is mutated
in retinoblastoma. For example, re-introduction of RB1 gene
into retinoblastoma cells and other RB1-deficient tumors28
sup-
pressed the neoplastic phenotype, indicating that the RB1 gene
was indeed a tumor suppressor. Thus, by the early 1990s, there
Fig. 128.2 RB gene, mRN
protein.
RB gene
(~ 200 kilobases)
27 exons
Coding region
ATG
Start
TGA
Stop
E2F
site
LXCXE
site
Tertiary
structure:
Binding
domains:
Noncoding region
3'5'
3'5'
RB mRNA
(4.7 kilobases)
RB protein
(928 amino acids)
A box B box
B boxA box
E2XF binding
LXCXE binding MDM2
Repression c-Abl
N-terminus
C-terminus
10. RETINOBLASTOMA GENE
➤ Functions to inhibit the cell cycle
from G1 to S-phase.
➤ Interacts with an important
transcription factor E2F.
➤ This tumor suppressor gene was
found to be mutated in many
cancers including breast and lung.
➤ So why does the retinoblastoma
gene mutations result primarily in
retinoblastoma?
- Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
- Ihab Saad Othman,Retinoblastoma major review with updates on Middle East management protocols,Saudi Journal of Ophthalmology, Volume 26, Issue
2,2012,Pages 163-175,ISSN 1319-4534,https://doi.org/10.1016/j.sjopt.2012.03.002.
TumorsoftheRetina
TumorsoftheRetina,Choroid,andVitreous
pRb to inhibit the G1-to-S phase transition of the cell cycle.82,83
But how does pRb actively represses transcription? In a series of
landmark papers, several groups showed that pRb binds to and
recruits to promoters proteins that alter chromatin structure,
such as histone deacetylases,83–85
SWI-SNF ATPases,86–88
DNA
methyltransferases,89
polycomb complexes,90
and histone meth-
ylases.91
Alteration of local chromatin structure into a restricted
conformation prevents access by the transcriptional machinery,
thereby inhibiting expression, whereas dynamic reorganization
of chromatin into an open configuration allows gene transcrip-
tion. Depending on the nature of the chromatin-remodeling
complex that pRb recruits, the cell cycle inhibition can be tem-
porary, as occurs during the quiescent period between cell divi-
sions, or permanent, as occurs during cell differentiation and
senescence.92
Studies of the tertiary (three-dimensional) structure of the pRb
protein have provided insights into how the protein performs
these complex functions (Fig. 128.2). The central region of the
pRb protein contains the A box and B box, which are highly
conserved from human to plants. These regions interact with
each other along an extended interdomain interface to form the
A–B pocket. The pocket is critical for the tumor suppressor func-
tion of pRb, and is disrupted by most germ line mutations in
hereditary retinoblastoma patients and somatic mutations in
tumors.29,93
The pocket is required for binding to E2F, chromatin
remodeling enzymes, viral oncoproteins, and other molecules.
Many pRb-binding proteins contain an LxCxE (leucine – variable
amino acid – cysteine – variable amino acid – glutamic acid)
accumulates in cycling cells as they enter DNA synthesis (S)
phase (Fig. 128.3).59–63
The hypophosphorylated form of pRb
bindsseveralviraloncoproteins,includingSV40largeTantigen,64
adenoviral E1a,65
and human papillomavirus E7.66
When bound
topRb,theseoncoproteinsstimulatecelldivision.Takentogether,
these findings provide evidence that hypophosphorylated pRb
is important in negatively regulating the cell cycle, and that this
inhibitory activity can be thwarted either by phosphorylation or
viral oncoprotein binding. Further work has shown that the
major cell cycle function of pRb is to inhibit the transition of cells
out of gap 1 (G1) phase into S phase.67
However, pRb may also
have roles in other cell cycle phases.68,69
A major breakthrough in understanding how pRb regulates
the cell cycle was the observation that pRb binds to members of
the E2F transcription factor family (referred to here as E2F).70–72
Further work has shown that pRb function is largely dependent
on interactions with E2F.73
E2F sites are found in the promoters
of many genes that are important for cell cycle progression, and
pRb represses transcription of these genes through its interaction
with E2F.74–77
Since E2F (but not pRb) has a DNA binding domain,
the pRb-E2F association would explain how pRb is brought to
specific DNA elements to exert its effect. Most E2Fs have a trans-
activation domain that stimulates expression of genes containing
E2F binding sites in their promoters. pRb binds E2F within the
transactivation domain,78,79
thereby masking its activity. Since
E2F activates genes involved in cell division,74,80
inhibition of E2F
provided a mechanistic explanation for how pRb inhibited cell
division. However, the picture became more complicated with
Fig. 128.3 Role of the Rb protein in the cell cycle and apoptosis.
HDAC
E2F
Rb
E2F
Rb
Rb
E2F
Rb
P P P
P
P P P
P
cdk4
p16
cyclin D
Rb pathway
mutation
Normal
cell cycle
Free E2F
Proliferation Apoptosis
Mitosis
DNA
synthesis
phase
cdk2
cyclin E
11. RETINOBLASTOMA: RISK FACTORS
➤ Unknown
➤ ? Maternal diet
➤ ? Viral infections (HPV)
➤
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
12. ZIMMERMAN FAMILY
➤ Pioneer in the field of ocular pathology especially retinoblastoma.
➤ His youngest son “Larry” was diagnosed with bilateral
retinoblastoma in 1967.
➤ At the time, mainstay of treatment was enucleating the eye with
more advanced tumor and treating the other eye with radiation.
➤ However, wanted to save the vision of his own son. First trial of
intracarotid chemotherapy by Drs Algernon Reese and Robert
Ellsworth in New York.
➤ This failed and so experimented with external beam radiotherapy
for the first time. This saved his eyes and vision (OD CF, OS
20/40).
Collins MLZ. Retinoblastoma: The Zimmerman Family Story. JAMA Ophthalmol. 2014;132(5):519–520. doi:10.1001/jamaophthalmol.2014.467
13. ZIMMERMAN FAMILY
➤ Larry worked as a banker in Manhatten and after genetic testing for the RB gene, decided with
his wife “Anne” to have a child.
➤ Perry was born, but developed bilateral retinoblastoma at 7 weeks, which was treated with laser
therapy by Dr David Abramson.
➤ For their second child, they underwent “pre-implantation genetic diagnosis” and had a safe
child.
➤ Perry unfortunately later on developed pinealoblastoma (but Prof Zimmerman knew this as his
own son working in his lab identified reminants of photoreceoptors in the pineal gland).
➤ Prof Zimmerman proposed the name “Trilateral disease”.
➤ Perry underwent also intrathecal chemotherapy for the first time to treat the pinealoblastoma
and she survived trilateral disease.
➤ She also developed osteosarcoma of the femur but is still alive.
Collins MLZ. Retinoblastoma: The Zimmerman Family Story. JAMA Ophthalmol. 2014;132(5):519–520. doi:10.1001/jamaophthalmol.2014.467
14. PRESENTING SIGNS
AAO BCSC 2015: Ophthalmic pathology and intraocular tumors - Retinoblastoma
examination with documented visual acuity. An examination under anesthesia (EUA) is
needed in all patients suspected ofhaving retinoblastoma to permit a complete assessment
of the extent of ocular disease prior to treatment (Fig 19-3). The intraocular pressure and
Table 19-2 Presenting Signs of Retinoblastoma
Among Patients <5 Years of Age
Leukocoria
Strabismus
Ocular inflammation
Hypopyon
Hyphema
Iris heterochromia
Spontaneous globe perforation
Proptosis
Cataract
Glaucoma
Nystagmus
Tearing
Anisocoria
Among Patients Years of Age
Leukocoria (35%)
Decreased vision (35%)
Strabismus (15%)
Floaters (5%)
Pain (5%)
15. DDX
AAO BCSC 2015: Ophthalmic pathology and intraocular tumors - Retinoblastoma
CHAPTER 19: Retinoblastoma • 305
Table 19-3 Differential Diagnosis of Retinoblastoma
Clinical Diagnosis in Pseudoretinoblastoma 265 Cases* Percent 76 Casest Percent
Persistent feta l vasculature 51 19 15 20
Retinopathy of prematurity 36 13 3 4
Posterior cataract 36 13 5 7
Coloboma of choroid or optic disc 30 11 7 9
Uveitis 27 10 2 3
Larval granulomatosis (Toxocara) 18 6 20 26
Congen ital reti nal fold 13 5
Coats disease 10 4 12 16
Organizing v it reous hemorrhage 9 3 3 4
Reti nal dysplasia 7 2
*Modified from Howard GM, Ellsworth RM. Differential diagnosis of retinoblastoma. Am J Ophthalmol.
1965;60:61 0-618.
t From Shields JA, Stephens RT, Sarin LK. The differential diagnosis of retinoblastoma. In: Harley RD, ed.
Pediatric Ophthalmology. 2nd ed. Philadelphia: Saunders; 1983:114.
remnants arising from the optic nerve head, usually in association with a closed funnel
16. CLASSIFICATION
➤ Reese–Ellsworth classification (1964): Predicts ocular salvage following external
beam radiation which was the main modality of treatment Before the 1990s.
➤ No prediction on survival.
➤ In 1989, chemotherapy was introduced and after a series of classifications, the
international classification of retinoblastoma was introduced.
Reese AB, Ellsworth RM. Management of retinoblastoma. Ann N Y Acad Sci 1964;114:958–62
17. CLASSIFICATION
AAO BCSC 2015: Ophthalmic pathology and intraocular tumors - Retinoblastoma
Reese A B. Tumors ofthe Eye. 3rd ed. Hagerstown, M D : Harper & Row; 1976:pp 90-132.
Shields CL, Mashayekhi A, D emirci H, M eadows AT, Shields JA. Practical approach to man-
agement of retinoblastoma. Arch Ophthalmol. 2004;122(5):729-735.
Table 19-5 International Classification System for Response to Chemotherapy
Group A
Group B
Group C
Group D
GroupE
Small tumors (s;3 mm) confined to the retina; >3 mm from the fovea; >1.5 mm from
the optic disc
Tumors (>3 mm) confined to the retina in any location, with clear subretinal fluid
s;6 mm from the tumor margin
Localized vitreous and/or subretinal seeding (<6 mm in total from tumor margin).
If there is more than 1 site of subretinal/vitreous seeding, then the total of these
sites must be <6 mm.
Diffuse vitreous and/or subretinal seeding mm in total from tumor margin). If
there is more than 1 site of subretinal/vitreous seeding, then the total of these
sites must be mm. Subretinal fluid >6 mm from tumor margin.
No visual potential; or
• Presence of any 1 or more of the following:
• tumor in the anterior segment
• tumor in or on the ciliary body
• neovascular glaucoma
• vitreous hemorrhage obscuring the tumor or significant hyphema
• phthisical or pre-phthisical eye
• orbital cellulitis-like presentation
18. CLASSIFICATION
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
2115
Chapter128Retinoblastoma
excellent vision are both high. In intraocular group A eyes, the
lesions are small and are away from critical visual structures
(foveola and optic nerve). Groups A and B contain all eyes in
which the tumor remains confined to the retina. In groups C and
D eyes, the tumor has spread into the vitreous and subretinal
space. In the case of group C eyes the spread is local. In the case
of group D eyes the seeding is diffuse (Fig. 128.7). Group E eyes
as the primary treatment. Letters “A” through “E” instead of
numbers were chosen to designate each classification group to
avoid confusion with the Reese–Ellsworth system. The risk of
loss of the eye due to retinoblastoma is graduated from “very
low” for Group A to “very high” for Group E.
In this classification, the letter “A” is assigned to those eyes
for which both the likelihood of curing the tumor and retaining
A B
C D
2115
Chapter128Retinoblastoma
excellent vision are both high. In intraocular group A eyes, the
lesions are small and are away from critical visual structures
(foveola and optic nerve). Groups A and B contain all eyes in
which the tumor remains confined to the retina. In groups C and
D eyes, the tumor has spread into the vitreous and subretinal
space. In the case of group C eyes the spread is local. In the case
of group D eyes the seeding is diffuse (Fig. 128.7). Group E eyes
as the primary treatment. Letters “A” through “E” instead of
numbers were chosen to designate each classification group to
avoid confusion with the Reese–Ellsworth system. The risk of
loss of the eye due to retinoblastoma is graduated from “very
low” for Group A to “very high” for Group E.
In this classification, the letter “A” is assigned to those eyes
for which both the likelihood of curing the tumor and retaining
A B
C D
A B
C
E
D
Fig. 128.7 Photographs depicting groups A to E; intra
retinoblastoma as described in the new group classifi
(for details see text).
2115
Chapter128Retinoblastoma
excellent vision are both high. In intraocular group A eyes, the
lesions are small and are away from critical visual structures
(foveola and optic nerve). Groups A and B contain all eyes in
which the tumor remains confined to the retina. In groups C and
D eyes, the tumor has spread into the vitreous and subretinal
space. In the case of group C eyes the spread is local. In the case
of group D eyes the seeding is diffuse (Fig. 128.7). Group E eyes
as the primary treatment. Letters “A” through “E” instead of
numbers were chosen to designate each classification group to
avoid confusion with the Reese–Ellsworth system. The risk of
loss of the eye due to retinoblastoma is graduated from “very
low” for Group A to “very high” for Group E.
In this classification, the letter “A” is assigned to those eyes
for which both the likelihood of curing the tumor and retaining
A B
C D
A B
C
E
D
Fig. 128.7 Photographs depicting groups A to E; intraocular
retinoblastoma as described in the new group classification
(for details see text).
19. NATURAL HISTORY
➤ Intra-retinal tumor
➤ Angiogenesis with feeder artery and draining vein.
➤ Loss of cellular adhesion and begin to seed into the vitreous (endophytic) and subretinal
spaces (exophytic with RD)
➤ Invasion of the choroid and optic nerves and into the brain
➤ Continued growth may induce glaucoma
➤ Ruptures the globe and see into the orbit or periorbital tissue.
➤ Distant metastasis is rare nowadays.
➤ Spontaneous regression in 5%
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
20. VARIANT: DIFFUSE RETINOBLASTOMA
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
2142
Section1TumorsoftheRetina
TumorsoftheRetina,Choroid,andVitreous
In 400 consecutive retinoblastoma patients, 34 were found to
be 5 years of age or older at the time of initial diagnosis.375
In
that series, the tumor was active retinoblastoma in 26 of the 34
unilaterally only, and prognosis after enucleation is good.366
Authors from Taiwan reported one hereditary case.367
This type
of retinoblastoma can also present with a hyphema.364,368
Gross-
Fig. 128.26 Diffuse
infiltrating
retinoblastoma.
(A) Unusual
tractional and
exudative retinal
detachment in
a 4-year-old.
(B) B-scan
ultrasonography
showed no calcium.
(C) Fluorescein
angiogram
resembles Coats
disease.
(D) Histopathology
revealed
retinoblastoma
involving the entire
retina. Subretinal
fluid and exudate
was present.
A
B
C D
21. DIAGNOSIS - EXAMINATION
➤ Typically EUA
➤ Look for anterior segment invasion (pseudohypopyon), cataract, and neovascular
glaucoma.
➤ Measure IOP (CD and AL if glaucoma is suspected)
➤ Dilated fundus examination + RetCam
➤ B-scan: To demonstrate intraocular calcification
➤ FFA, useful in:
➤ 1) Diagnosis of NVI
➤ 2) Recurrent tumors (Leakage and staining of active lesions; whereas inactive lesions
do not).
➤ 3) Uncertain with the diagnosis: Retinomas do not leak nor stain.
AAO BCSC 2015: Ophthalmic pathology and intraocular tumors - Retinoblastoma
Figure 3-9. Elastosis demonstrating basophilic degeneration of conjunctival
substantia propria in a pinguecula. (From Yanoff M, Fine BS: Ocular
pathology, 5th edn. St Louis, Mosby, 2002.)
Box 3-1. Differential diagnostics of intraocular calcification
Retinoblastoma
Choroidal osteoma
Choroidal hemangioma
Phthisis
Osseous choristoma
Box 3-2. Differential diagnostics of intraocular cartilage
PHPV (retrolental plaque)
Medulloepithelioma
Teratoma
Trisomy 13 (Figure 3-10)
Complex choristoma of conjunctiva
AGING CHANGES
Cornea: Hassal-Henle warts (excrescences and thickenings
of Descemet’s membrane in corneal periphery)
Ciliary epithelium: hyperplasia and proliferation
Pars plana and pars plicata: clear (teardrop) cysts
Retina: loss of retinal cells and replacement with glial
tissue; chorioretinal adhesions and pigmentary lesions in
periphery; peripheral microcystoid degeneration (Blessig-
Iwanoff cysts): located in outer plexiform layer; bubbly
appearance just behind ora serrata; lined by Müller cells;
contain mucopolysacharides
WOUNDS
Wound Healing
Cornea: stromal healing is avascular; fibrosis; neutrophils
arrive via tears in 2–6 hours; wound edges swell and
glycosaminoglycans (keratan sulfate, chondroitin sulfate)
disintegrate at edge of wound; activated fibroblasts migrate
are removed by phagocytic and biochemical processes
Hemosiderosis bulbi: hemosiderin contains iron; can
damage essential intracellular enzyme systems
Ochre membrane: hemorrhage that accumulates on
posterior surface of detached vitreous
Synchysis scintillans: accumulation of cholesterol within
vitreous following breakdown of red blood cell (RBC)
membranes; angular, birefringent, flat crystalline
particles with golden hue located in dependent
portions of globe; cholesterol dissolves during
preparation of tissues in paraffin; cholesterol clefts are
negative image of cholesterol crystals, surrounded by
serous fluid
22. DIAGNOSIS - INVESTIGATIONS
➤ If B-scan does not demonstrate the hyperreflective echos of calcifications (sign of
intra-ocular necrosis or if diagnosis is in doubt, then CT scan may be ordered).
➤ However, CT is better avoided in cases of bilateral retinoblastomas due to the
risk of secondary cancers.
➤ Neuroimaging; MRI in order to:
➤ Look for invasion of the choroid, optic nerve.
➤ Exclude trilateral disease.
➤ FNA is contraindicated expect if diagnosis is really in doubt like uveitis in an
older child. Although specular microscopy may be useful.
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
23. DIAGNOSIS - INVESTIGATIONS
➤ If MRI show extraocular spread then:
➤ CBC
➤ Bone marrow biopsy (several places)
➤ Bone scan
➤ CSF analysis
➤ Common metastatic sites: CNS, Bone, spleen.
AAO BCSC 2015: Ophthalmic pathology and intraocular tumors - Retinoblastoma
24. DIAGNOSIS - MANAGEMENT
➤ Staging EUA
➤ NOT A GOOD IDEA TO ENUCLEATE AT THE TIME OF STAGING EUA.
➤ Treat the child, not the eye!
25. DIAGNOSIS - MANAGEMENT
➤ Save life
➤ Save eye
➤ Save sight
Multidisciplanary approach including, pediatrician, oncologist, ophthalmologist,
geneticist.
26. DIAGNOSIS - MANAGEMENT
Treatment modalities:
➤ Photocoagulation
➤ Thermotherapy
➤ Cryotherapy
➤ Brachytherapy (better than external beam radiontherapy EBRT).
➤ External beam radiotherapy
➤ Systemic chemotherapy (carboplatin, etoposide, vincristine)
➤ Sub-tenon chemotherapy
➤ Intravitreal chemotherapy
➤ Enucleation
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
27. CRYOTHERAPY
➤ Destroys tumor by:
• Destruction of the cellular membranes during freeze-thaw cycle
• Vaso-occulsion
➤ 3 cycles
➤ Complications:
• Freezing the optic nerve
• Vitreous hemorrhage, subretinal fluid, and retinal holes and retinal detachment
•
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
28. SYNERGISTIC EFFECT OF CARBOPLATIN AND HEAT
➤ Heating the tumor to a particular temperature can induce necrosis (e.g.
photocoagulation with temperature rise to 60-70 0C)
➤ However, heating the tumor to 40-44 0C may enhance treatment success with
systemic carboplatin by:
• Enhanced drug uptake
• Apoptosis
• Modulation of drug resistance
Photocoagulation has both effects.
Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol 2002;43:33–56
Necrosis Heat (1-2mm)
29. PHOTOCOAGULATION
➤ Argon 532um
➤ Power 250-300mw and duration
300-500ms.
➤ Complications in the in-
experienced hands:
• Iridocyclitis
• Vitreous hmg
• Tumor seeding
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
Retinoblasto
Fig. 128.15 Technique for laser focal consolidation. 1. First burns are
placed at the edge of the lesion with the spot half on and half off the
tumor. 2. The lesion is then outlined with 30% overlap of the previous
spot. 3. The lesion is then painted with 30% overlap.
2
1
3
with the beginning of the 2nd or 3rd cycle of systemic chemo-
therapy after the tumor volume has been reduced. The goal of
the therapy is to completely cover each lesion with 30% overlap
during at least three different sessions. We choose initial power
setting of 250–300 mW, with a duration of 300–500 msec. The
power and time settings are kept low to prevent tumor disrup-
tion and hemorrhage that may be associated with excessive
energy delivery. The first burns are placed at the edge of the
lesion with the spot half on and half off the tumor. The power
and/or duration can be adjusted to achieve gentle whitening of
the tumor. We do not recommend exceeding 500–600 mW and
700 msec with the 532 mm laser. Once the lesion is outlined, then
the entire lesion including any type I regression-associated
calcium is covered with overlapping rows of burns (Fig. 128.15).
A small to moderate-sized lesion may require 200–400 burns for
good coverage. The burns over the thicker areas of the tumor
may be virtually invisible compared with those placed at the
edge of the lesion. The power or duration should not be increased
to compensate for the decreased “take” over the thicker parts of
the lesion. Repeat the laser coverage at 2–4-week intervals during
and/or after the administration of systemic chemotherapy until
the entire lesion has been covered on at least three different
occasions (Fig. 128.16).
Because the infrared 810-nm diode laser has a longer wave-
length than the argon laser, it penetrates further and is absorbed
mainly by the retinal pigment epithelium. It is useful primarily
if retinal pigmented epithelium (RPE) is intact under the lesion
to be treated. One major advantage of the infrared laser is its
iris at the pupillary margin and focal lens opacities, both of
which are very rare in experienced hands. Other complications
that are associated with excessive energy delivered to the tumor
include subhyaloid and vitreous hemorrhage. Theoretically, it is
30. RADIATION THERAPY
External beam radiotherapy
➤ High risk of secondary primary tumors in germline retinblastomas
➤ Now used when chemotherapy fails or extraocular disease in most centers.
Intensity modulated radiation therapy
Proton beam radiotherapy
Brachytherapy
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
31. INTRARTERIAL CHEMOTHERAPY
➤ First tried at New York (1960s) by Reese and Ellsworth : Intracarotid
chemotherapy which was not successful.
➤ Kaneko in 1980s (the National Cancer Institute in Tokyo, Japan): developed
selective ophthalmic arterial infusion (SOAI) to salvage group E.
➤ Abramson (New York) modified the technique in 2008.
Hyman GA, Ellsworth RM, Feind CR, et al. Combination therapy in retino- blastoma. A 15-year summary of methods and results. Arch Ophthalmol 1968;80:744–6.
Yamane T, Kaneko A, Mohri M. The technique of ophthalmic arterial infusion therapy for patients with intraocular retinoblastoma. Int J Clin Oncol 2004;9:69–73
Abramson DH. Super selective ophthalmic artery delivery of chemotherapy for intraocular retinoblastoma: ‘chemosurgery’ the rst Stallard lecture. Br J Ophthalmol
2010;94:396–9.
32. INTRAVITREAL CHEMOTHERAPY
➤ Intraocular surgery was previously forbidden in retinoblastoma given the risk of
seeding.
➤ Diffuse intravitreal seeding of retinoblastoma pose a challenge given the low
blood supply and not responding to cryo or laser.
➤ Previously EBRT was used.
➤ Recently intravitreal melphelan was used to treat recurrent or resistant vitreal
seeds with 100% success rate.
Manjandavida FP, Shields CL. The role of intravitreal chemotherapy for retinoblastoma. Indian Journal of Ophthalmology. 2015;63(2):141-145. doi:
10.4103/0301-4738.154390.
33. MANAGEMENT
➤ Unilateral disease:
➤ Group A: Photocoagulation and/or cryotherapy
➤ Group B: Chemoreduction followed by focal consolidation. Plaque radiotherapy
may be used in peripheral lesions.
➤ Group C: If useful vision, chemotherapy followed by focal consolidation.
➤ Group D: unlikely to benefit from chemo and other treatment modalities given
that the other eye is ok.
➤ Group E: Enucleation
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
34. DIAGNOSIS - MANAGEMENT
➤ Bilateral disease:
➤ More complicated
➤ Symmetrical vs asymmetrical disease in the eyes
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
35. REGRESSION PATTERNS AFTER PRIMARY
SYSTEMIC CHEMOTHERAPY
2135
Chapter128Retinoblastoma
Table 128.2 Tumor regression patterns following
primary chemotherapy
Type Description
Needs
consolidation
0 Small intraretinal lesion
that disappears completely
without RPE changes
No
I Entire lesion calcifies into a
mass that looks like
“rock-salt.” RPE changes
at base
Probably yes
II Homogenous semi-
translucent, gray “fish-
flesh” lesion
Yes
III A combination of type I
and type II. This is the
most common regression
pattern
Yes
IV An entirely flat chorioretinal
scar with significant RPE
changes, most commonly
seen after laser
consolidation
Yes, three
complete laser
coverages
Early retinoma
retinocytoma
Looks like type II
regression prior to
treatment with
chemotherapy or
radiotherapy and shows no
change during or following
treatment. May contain
cystic or cavitary spaces
Unknown
RPE, retinal pigmented epithelium.
secondary enucleation did not add to the bony growth retar-
dation triggered by external beam radiotherapy. Not surpris-
ingly, these authors observe the growth-impairing effect of
EBR to be most profound when the child is irradiated before
6 months of age (P<0.01).302
When reports assume that both
enucleation and radiation contribute to retardation of orbital
growth and do not differentiate between the two, confusion
is the outcome.303
Orbital growth studies in rabbits show a
decelerated increase in orbital mass following enucleation that
was mitigated by an expandable but not static orbital implant.304
Based on the findings of Fountain et al. growth in enucleated
human orbits may be normal if a large but nonexpandable
orbital implant is used.300
Follow-up after enucleation varies from center to center. We
do not currently order MRI scans more than once yearly except
when heritable disease is diagnosed before 12 months of age. In
that case, we do MRI every 6 months until age 3, looking for
possible midline PNET. The generally recognized risk period for
extraocular spread after successful treatment or enucleation is
12–18 months.
Retrolaminar optic nerve involvement
If a pathologic evaluation demonstrates optic nerve involvement
beyond the lamina cribrosa and massive choroidal invasion, 6
months of adjuvant chemotherapy is recommended by some
centers but not all. Chantada and colleagues question the need
for this adjuvant therapy.207
The initial series reporting the risk
of retrolaminar optic nerve involvement came from New York
in 1989.305
It is instructive that currently in New York, this group
is not treating retrolaminar retinoblastoma with adjuvant
chemotherapy.
The chemotherapy protocol commonly used for adjuvant
therapy is the combination of carboplatin, etoposide, and vin-
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous
in Retina (5th Edition). 2013
2136
Section1TumorsoftheRetina
TumorsoftheRetina,Choroid,andVitreous
In our experience, focal regrowth or edge recurrence is usually
seen within 2–6 months following the completion of chemo-
therapy (Fig. 128.24). However, we have treated patients in Los
Angeles where some of these eyes were later enucleated. Others
have been treated successfully with additional CEV and aggres-
sive focal consolidation. Serial RetCam images are essential for
good follow-up. Early focal regrowth usually appears as a slight
eyes with no recurrence from type IV regression by 6.5 years
following treatment. Type I was the most common regression
pattern with fewer type II and III. These authors make a point
of referring to the regression types as “radiation” regression
patterns.
New tumors or tumor recurrences during
Fig. 128.23 Regression patterns I–IV after treatment of retinoblastoma.
A B
C D
36. IN CASE OF GROUP E
➤ Enucleated eyes are examined for optic nerve invasion
37. HISTOLOGY
AAO BCSC 2015: Ophthalmic pathology and intraocular tumors - Retinoblastoma
CHAPTER 11: Retina and Retinal Pigment Epithelium • 179
Figure 11-38 Retinoblastoma. Note the viable tumor cells (asterisk) surrounding a blood ves-
sel (arrow) and the alternating zones of necrosis (N). This histologic arrangement is referred
to as a pseudorosette.
tumor cells surrounding a blood vessel); calcification is a common finding in areas of ne-
crosis (Fig 11-39). Cuffs ofviable cells course along blood vessels with regions ofischemic
necrosis beginning 90-120 flm from nutrient vessels. DNA released from necrotic cells
may be detected within tumor vessels and within blood vessels in tissues remote from
the tumor, such as the iris. Neovascularization of the iris can complicate retinoblastoma
(Fig 11-40).
Cells shed from retinoblastoma tumors remain viable in the vitreous and subretinal
space, and they may eventually give rise to implants throughout the eye. It may be difficult
Figure 11-38 Retinoblastoma. Note the viable tumor cells (asterisk) surrounding a blood ves-
sel (arrow) and the alternating zones of necrosis (N). This histologic arrangement is referred
to as a pseudorosette.
tumor cells surrounding a blood vessel); calcification is a common finding in areas of ne-
crosis (Fig 11-39). Cuffs ofviable cells course along blood vessels with regions ofischemic
necrosis beginning 90-120 flm from nutrient vessels. DNA released from necrotic cells
may be detected within tumor vessels and within blood vessels in tissues remote from
the tumor, such as the iris. Neovascularization of the iris can complicate retinoblastoma
(Fig 11-40).
Cells shed from retinoblastoma tumors remain viable in the vitreous and subretinal
space, and they may eventually give rise to implants throughout the eye. It may be difficult
Figure 11-39 Retinoblastoma. Zones of viable tumor (usually surrounding blood vessels) alter-
nate w ith zones of tumor necrosis (asterisk). Calcium (arrow) is present in the necrotic area.
The basophilic material surrounding the blood vessels is DNA, presumably liberated from the
necrotic tumor.
CHAPTER 11 : Retina and Retinal Pigment Epithelium • 181
Figure 11-41 Retinoblastoma rosettes. A, Flexner-Wintersteiner rosettes: note the central
lumen (L). B, Homer Wright rosettes: note the neurofibrillary tangle (arrow} in the center of
these structures. C, The fleurette (arrow} demonstrates bulbous cellular extension of retino-
blastoma cells that represent differentiation along the lines of photoreceptor inner segments.
38. COMPLICATIONS OF CHEMOTHERAPY
➤ General: bone marrow suppression, alopecia and central line infections
➤ Etoposide: AML
➤ Carboplatin: Hearing loss
Suggestion of chemo reducing trilateral disease.
Shields CL, Meadows AT, Shields JA, Carvalho C, Smith AF. Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy
(trilateral retinoblastoma). Arch Ophthalmol. 2001;119(9):1269-1272.
39. LATE COMPLICATIONS
➤ Bone hypoplasia
➤ Cataract
➤ Radiation retinopathy
➤ Neuro-cognitive deficits
➤ Second malignant (primary) tumors
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
40. METASTASIS - HIGH RISK RETINOBLASTOMA
Risk factors
➤ Before enucleation
➤ Anterior segment involvement: NVI, ectropion uvea, pseudohypopyon.
➤ After enucleation
➤ Invasion of the optic past the lamina cribrosa
➤ Massive choroidal invasion
➤ Extraocular invasion
Metastasis only occurs in a subset of tumors with metastatic potential.
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
41. SURVIVAL FROM RETINOBLASTOMA
➤ If still intraocular 95%
➤ If extrocular invasion 50%
However, second primary tumors.
AAO BCSC 2015: Ophthalmic pathology and intraocular tumors - Retinoblastoma
42. SECOND PRIMARY TUMORS
➤ In the field of radiation
• Osteosarcoms
• Leimyosarcomas
• Fibrous histeocytomas
➤ Away from the field of radiation
• Osteosarcomas
• Renal cell carcinoma, Ewing’s sarcoma, carcinoma of the tongue, and
medulloblastoma.
•
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
43. SECOND PRIMARY TUMORS
Tamara Marees, Annette C. Moll, Saskia M. Imhof, Michiel R. de Boer, Peter J. Ringens, Flora E. van Leeuwen; Risk of Second Malignancies in Survivors of Retinoblastoma: More Than
40 Years of Follow-up, JNCI: Journal of the National Cancer Institute, Volume 100, Issue 24, 17 December 2008, Pages 1771–1779, https://doi.org/10.1093/jnci/djn394The cumulative incidence of a second malignancy at 40 years 13.3% (95% CI = 3.28% to 23.3%) for nonirradiated hereditary
Table 2. Risk of second malignancies in Dutch retinoblastoma patients by heredity*
Hereditary retinoblastoma patients† Nonhereditary retinoblastoma patients‡
Cancer site (ICD-O-2 classification) O SIR (95% CI) AER O SIR (95% CI) AER
All sites†,§ 62 20.4 (15.6 to 26.1) 8.61 12 1.86 (0.96 to 3.24) 0.57
Bone (170) 16 314 (180 to 511) 2.33 0 0 (0 to 86.5) 0
Soft tissue (171) 20 243 (148 to 375) 2.91 3 21.8 (4.50 to 63.7) 0.29
Skin melanoma (172) 13 50.8 (27.0 to 86.8) 1.86 1 1.97 (0.05 to 11.0) 0.05
Solid cancers (excluding bone,
soft tissue, and melanoma)
11 5.06 (2.52 to 9.05) 1.29 5 1.01 (0.33 to 2.36) 0.01
Bladder (188) 4 124 (34.0 to 319) 0.58 0 0 (0 to 59.2) 0
Lung (162) 3 16.8 (3.47 to 49.2) 0.41 2 4.08 (0.50 to 14.7) 0.15
Breast (174) 2 2.95 (0.36 to 10.7) 0.19 1 0.62 (0.02 to 3.47) Ϫ0.06
Non-Hodgkin lymphoma (200, 202) 2 13.8 (1.67 to 49.9) 0.27 0 0 (0 to 21.4) 0
Leukemia (204–207) 0 0 (0 to 17.8) 0 2 6.58 (0.79 to 23.75) 0.17
* ICD-O-2 = International Classification of Diseases for Oncology; O = observed number of cases; SIR = standardized incidence ratio; CI = confidence interval;
AER = absolute excess risk (observed numbers of cancers minus expected number of cancers per person-years multiplied by 1000).
† n = 298 with 6848 person-years at risk.
‡ n = 370 with 9804 person-years at risk.
§ Cancer sites not listed for hereditary patients include one of brain (ICD-O-2 191.9, SIR = 6.85, 95% CI = 0.17 to 38.1, AER = 0.12 per 1000 person-years) and
one other malignant neoplasm of skin (ICD-O-2 173.1). Cancer sites not listed for nonhereditary retinoblastoma includes one Hodgkin lymphoma (ICD-O-2 201.9,
SIR = 5.54, 95% CI = 0.14 to 30.9, AER = 0.08 per 1000 person-years), one squamous cell carcinoma of skin (OCD-O-2 173.3), and one cancer not otherwise
specified (ICD-O-2 199.1).
44. MORTALITY FROM SECONDARY TUMORS
Charis Eng, Frederick P. Li, David H. Abramson, Robert M. Ellsworth, F. Lennie Wong, Marlene B. Goldman, Johanna Seddon, Nancy Tarbell, John D. Boice; Mortality From
Second Tumors Among Long-Term Survivors of Retinoblastoma, JNCI: Journal of the National Cancer Institute, Volume 85, Issue 14, 21 July 1993, Pages 1121–1128, https://doi-
org.ezproxy.auckland.ac.nz/10.1093/jnci/85.14.1121
All tumors other than Rb
Excess nsk per 1000
person-years
85 1.3
5.8
63t 5 0.2
2.5
22t 2 0.4
0.8
5 4 1.2
0.2
3
•Deaths are those in the United States occurring after 1924. Rb = retinoblastoma.
IVEMORTALITYMULAT
O
30
25
20
15
10
5
0
BILATERAL
UNILATERAL
-
-
1
919
684
BILATERAL - •
/ UNILATERAL
y :-*-,-
10 20 30
TIME AFTER DIAGNOSIS (YR)
663 404 161
524 320 127
NUMBER OF CHILDREN WITH RETINOBLASTOMA
26.0 ±3.9%
1.5 ± 0.7%
_
-
-
40
36
43
Fig. 1. Cumulative mor-
tality from second primary
neoplasms during follow-up
of the entire cohort of 1603
retinoblastoma patients by
laterality (bilateral and
unilateral).
mortality from second primary neoplasms at 40 years of and extensive tracing efforts located 91% of them. Patients
45. MORTALITY FROM SECONDARY TUMORS
Charis Eng, Frederick P. Li, David H. Abramson, Robert M. Ellsworth, F. Lennie Wong, Marlene B. Goldman, Johanna Seddon, Nancy Tarbell, John D. Boice; Mortality From
Second Tumors Among Long-Term Survivors of Retinoblastoma, JNCI: Journal of the National Cancer Institute, Volume 85, Issue 14, 21 July 1993, Pages 1121–1128, https://doi-
org.ezproxy.auckland.ac.nz/10.1093/jnci/85.14.1121
ITY(<X)RTALTIVEUMULA
O
35
30
25
20
15
10
5
u
-
-
-
-
-
RADIOTHERAPY
NO RADIOTHERAPY
30.3 + 4.8%
RADIOTHERAPY -»•
/— NO RADIOTHERAPY
^ ^ - J i 6.4 ±3 8%_
_/ [
^j* i
, i
^J
'T
*i
I i i i i i
1 10 20 30 t
TIME AFTER DIAGNOSIS (YR)
(0
835 593 359 134 25
84 70 45 27 11
NUMBER OF CHILDREN WITH BILATERAL RETINOBLASTOMA
Fig. 2. Cumulative mor-
tality from second primary
neoplasms during follow-up
of bilateral retinoblastoma
patients by treatment with
and without irradiation.
further increased among the bilateral patients who received
radiotherapy. An excess mortality from second neoplasms
of small numbers (23,29,35,36,41). The excess tumors in
these studies were predominantly bone and soft tissue
46. TUMOR RECURRENCE/SECOND PRIMARY TUMORS
➤ Normally occur within 6 months of chemotherapy, however, may be more.
➤ F/U with EUAs every 3-6 months until the age of 3 and then annually until 18 years in the clinic
with indirect and B-scan.
➤ MRI for trilateral disease should be done annually until 5 years of age.
➤ Risk factor include early presentation and germ-line tumors.
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
2137
Chapter128Retinoblastoma
Fig. 128.24 (A) Type IV regression after primary chemotherapy and focal laser consolidation. (B) Edge recurrence seen 3 months later.
A B
follows these children as they become teenagers and young
adults. In 1991, 99 German patients treated for retinoblastoma
between 1965 and 1982 and examined in 1988, were reviewed to
311
Radiation cataract
Tolerance levels of ocular structures vary greatly. The lacrimal
gland, cornea, and conjunctiva can each tolerate up to 50 Gy
47. RETINOBLASTOMA AND LEUKEMIA
➤ Rare
➤ Reported Acute lymphoblastic and myeloblastic leukemia
Cancer Genet Cytogenet 49:15 23 (1990)
Structural Alterations at the Putative
Retinoblastoma Locus in Some Human
Leukemias and Preleukemia
Marc F. Hansen, Rodman Morgan, Avery A. Sandberg,
and Webster K. Cavenee
ABSTRACT: Homozygous loss of alleles of the retinoblastama susceptibility locus (RB 1) has been impli-
cated in the onset of many different solid tumors. Heterozygous deletions of chromosome 13q14,
the region containing the RB1 locus, have been observed by us in several subvariants of leukemia
and preleukemia. We examined four cases of leukemia and one case of preleukemia for homozy-
gous inactivation of the RB1 locus; in at least one case, evidence supports the concept that
homozygous loss of both alleles of RB1 was an important step during leukemogenesis.
INTRODUCTION
48. RETINOBLASTOMA AND LEUKEMIA
Current Topics ill Microbioloyy and Immunology, Vol. 182
Why Don't Germline Mutations
in RB1 Predispose to Leukemia?
R. A. PHILLlPS1,4,5, R. M. GILL1,5, E. ZACKSENHAUS5, R. BREMNER5, Z. JIANG5,
M. SOPTA5, B. L. GALLlE1,3,5 and P. A. HAMEL2
Departments of 1Medical Genetics, 2Pathology, 30phthalmology and
4lmmunology, University of Toronto, and 5Division of Immunology and Cancer
Research, The Hospital for Sick Children, Toronto, Canada M5G 1X8
Retinoblastoma and the RBI Gene
Retinoblastoma, a rare tumor of childhood, is interesting because it exists in both heritable
and non-heritable forms (for review see [1]). In the non-heritable form, affected individuals
develop only a single tumor in one eye. In contrast, in the heritable form, the affected
individuals develop multiple tumors usually affecting both eyes. Heritable retinoblastoma has
high penetrance with more than 90% of individuals carrying a germline mutation in the
retinoblastoma gene (RBJ) on chromosome 13 ultimately developing tumors. In addition,
patients with a germline RBJ mutation are susceptible to multiple other tumors, primarily
osteosarcoma, fibrosarcoma, melanoma, small cell carcinoma of the lung and bladder carcinoma
[2, 3]. However, such individuals appear not to have an increased risk for leukemias or other
malignancies of the hematopoietic system [4).
In 1971 Knudson proposed that only two mutations are necessary to convert a normal
retinal cell into a malignant retinoblastoma tumor cell [5). In normal individuals, both mutations
must occur in the same retinal progenitor cell. Since the time available for these mutations to
occur is relatively short (retinoblastoma seldom develops in children older than 3 years), few
individuals develop these mutations, and the incidence of retinoblastoma in the population is
489
conclusions are correct, then we must conclude that RBI mutations are not important in
leukemogenesis. That is, mutations in the RBI gene play no role in converting a normal
hematopoietic cell to a malignant cell. If RBI mutations could contribute to the initiation of
leukemia, retinoblastoma patients with germline mutations in RBi should have an increased
incidence of leukemia, and they do not. However, after a hematopoietic cell has become
malignant and escaped most growth control mechanisms, subsequent RB I mutations may
increase growth rates and contribute to progression of the malignant phenotype, perhaps by
altering c-myc expression.
Acknowledgements
The research described in this paper was supported by The National Cancer Institute of
Canada with funds from the Canadian Cancer Society and from the Terry Fox Marathon of
49. SURVEILLANCE OF SECOND PRIMARY TUMORS
➤ CT and bone scans pre-dispose to bone tumors
➤ MRI: Uncertain about its predictive value as many patients who develop second
primary tumors had normal MRIs 3-4 months earlier.
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
50. TAKE HOME MESSAGES
➤ Retinoblastoma is the most common intraocular tumor of childhood.
➤ Management requires multidisciplinary team with high expertise.
➤ Germline mutations require very close follow-up for recurrence of tumor and
development of second primary tumors.
Chapter
128
“If most solid tumors of childhood are indeed correctly
attributable to mutations in germ and/or somatic cells …
then childhood cancer cannot be prevented. … the main
effort against childhood cancer must be that of early
diagnosis and treatment”1
A. G. Knudson Jr, 1976
Retinoblastoma
Thomas C. Lee, Dan S. Gombos, J. W
Nancy C. Mansfield † (posthumously)
genes; an
retinobla
GENET
Clinica
Study of
genetic b
51.
52. VARIENTS: RETINOMA/RETINOCYTOMA
Stephen Ryan (Ed). Tumors of the retina, choroid and vitreous in Retina (5th Edition). 2013
2141
Chapter128Retinoblastoma
A B
C
Fig. 128.25 (A) Presumed retinoma. Appearance is similar to type II
regression prior to any treatment. (B) After focal laser consolidation it
begins to regress. (C) Several laser treatments later the tumor is
nearly flat.
diagnosis and then shows virtually no volume reduction after retinomas and vitreous seeding that were followed for 8 and