Author's Accepted Manuscript

Retinoblastoma: An update
Kushal S. Delhiwala MD, V.P. Indu MD,
Kaustubh Mulay MD, Vikas Khetan MD

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PII: S0740-2570(15)00142-2
DOI: http://dx.doi.org/10.1053/j.semdp.2015.10.007
Reference: YSDIA50433

To appear in: Seminars in Diagnostic Pathology

Cite this article as: Kushal S. Delhiwala MD, V.P. Indu MD, Kaustubh
Mulay MD, Vikas Khetan MD, Retinoblastoma: An update, Seminars in
Diagnostic Pathology, http://dx.doi.org/10.1053/j.semdp.2015.10.007

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 Delhiwala et al. Page 1

RETINOBLASTOMA: AN UPDATE
Kushal S. Delhiwala, MD1

Indu VP, MD1

Kaustubh Mulay, MD2

Vikas Khetan, MD1,3

1 – Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India.

2 – National Reporting Centre for Ophthalmic Pathology, Centre For Sight, Hyderabad

3 - Ocular Oncology Services and Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya,

Chennai, Tamil Nadu, India

Corresponding Author

Vikas Khetan, MD, Ocular Oncology Services and ShriBhagwanMahavirVitreoretinal Services,

SankaraNethralaya, Chennai - 600 006, Tamil Nadu, India (E-mail: drkhetan@yahoo.com)

Abstract

Retinoblastoma is the most common ocular malignancy in children, and is initiated by

mutation of the RB1 gene. The tumor may be unilateral or bilateral and can be

inherited. Overall survival, eye salvage, and preservation of vision are largely

dependent on the stage of disease at presentation. Despite a recently-enhanced

understanding of the etiology of retinoblastoma, the mortality associated with it remains

high worldwide. This may relate to a continuing lack of awareness of the lesion by

laypersons, and unavailability of modern treatment facilities. Adverse outcomes are

 Delhiwala et al. Page 2

also caused by the occurrence of secondary malignancies after treatment of

retinoblastoma in childhood. Early diagnosis, multidisciplinary treatment, and genetic

counselling are all priorities in the management of this tumor.

Key Words: Retinoblastoma; childhood neoplasms; ocular tumors; heritable neoplasms

Retinoblastoma (RB), which can be considered as a prototype of inherited

cancers, is the second most common intraocular malignancy after uveal melanoma. It is

the principal tumor seen in the eyes of children, in whom it represents 4% of all pediatric

malignancies.1 Despite being an aggressive disease, retinoblastoma has been

associated with good survival rates because of early detection and improving treatment

methods.2,3 Identification of genetic mutations that are associated with RB, recognition

of high-risk histopathologic factors, and aggressive multidisciplinary therapy have

contributed to better survival, eye salvage, and potential preservation of vision.

History, Epidemiology, & Classification

Retinoblastoma was first described by Pawius in 1597.4 Wardrop (1809) named it

“fungus hematoides,” and Virchow considered RB to be a glioma of the retina in 1864.4

The presence of rosettes in the tumor at a histological level prompted Flexner, in 1891,

and then Wintersteiner, in 1897, to designate RB as a neuroepithelioma.4 In 1926, the

American Ophthalmological Society agreed upon the term ‘retinoblastoma’ after a

consensus was reached that the tumor likely originated from the proliferation of

retinoblasts.5
 Delhiwala et al. Page 3

The incidence of retinoblastoma has been constant worldwide, at 1 case per

15,000-20,000 live births; that figure corresponds to 9000 new cases each year.6,7 The

populations of Asia and Africa account for the majority of these.6 RB in those continents

is also associated with high mortality rates, which are likely attributable to delayed

detection and inadequate treatment facilities. No significant racial or gender

predilection has been reported; bilaterality is seen in 25-35% cases.8 Sporadic

examples are unilateral, whereas familial tumors may either be unilateral or bilateral.9

The average age at diagnosis is 18 months-- 24 months for unilateral disease and 12

months for bilateral.10

Genetics

Of all newly diagnosed cases, 6% are inherited and the rest are sporadic.8,9

Retinoblastoma was the first disease in which a genetic basis for cancer was

identified—biallelic deactivation of the RB1 gene.6 In 1971, Knudson proposed the “2-

hit hypothesis” for RB development, and suggested that 2 mutational events were

necessary to that process.10 In familial cases, the initial event is a germline mutation,

found in all cells of the affected offspring; the second “hit” occurs during the

development of somatic retinal cells. By contrast, both mutations are somatic in nature

in sporadic tumors. This paradigm may also explain the high risk of secondary non-

ocular malignancies that is seen in patients with familial bilateral retinoblastoma.10,11

The RB1 gene has been mapped to the long arm of chromosome 13 (13q14).12

It is a negative cell-cycle regulator, maintaining a balance between cell proliferation and

development.13 RB-phosphoprotein, the gene product. acts to interrupt the transition

between the G1- and S-phases of the cell cycle. Its active form, pRB, is
 Delhiwala et al. Page 4

hypophosphorylated and seen in resting cells; on the other hand, proliferating cells

contain hyper-phosphorylated pRB (ppRB). Phosphorylation is inhibited by cyclin

dependent kinases (CDK). pRB blocks cell division by binding to transcription factor

E2F and preventing the transcription of cell cycle-related genes that are active in the

G1-S phase transition; ppRB has an opposing activity.

The loss of RB1 function initiates the formation of retinoblastoma but is

inadequate for complete development of that tumor; other genetic and epigenetic events

are necessary to that process.14 There is increasing evidence for a role of oncogenes

such as MDM4, KIF14, MYCN, DEK, and E2F3, and the tumor suppressor gene CDH11

in retinoblastomagenesis.12 Comparative genomic hybridization (CGH) has identified

gains in chromosomes 1q32, 2p24, 6p22, and losses in 13q and 16q22-24 in

retinoblastoma.12,15 Dysregulated genes in the insulin and JAK/STAT pathways have

likewise been identified.16 Epigenetic events in retinoblastoma include hypermethylation

of RB1 promoters; genes in the RAS association domain; MGMT; p16INK4; MSH6;

CD44; PAX5; GATA5; TP53; VHL; and GSTP1.12 Micro RNAs (miRNAs) may also be

differentially expressed in retinoblastoma.12,17

Matrix metalloproteinases (MMPs)-- which play a role in tumor invasion,

degradation of stroma, and angiogenesis-- are modified in retinoblastomas. Although

MMP-2 is observed in differentiated tumors, the expression of TIMP-1 and TIMP-2

predominates in primitive blastomatous neoplasms.18 Epithelial cell adhesion molecule

(EpCAM) appears to show greater expression in invasive tumors as compared with non-

invasive examples.19
 Delhiwala et al. Page 5

Clinical Manifestations

The clinical features of retinoblastoma largely depend on the stage of the disease

at presentation. Leucocoria is the commonest initial finding (seen in 60% of cases)

followed by strabismus (20%).20 Others include a painful blind eye, diminished vision,

orbital cellulitis, unilateral mydriasis, heterochromia iridis, and hyphema.21 The tumor

growth pattern may be endophytic (growth into the vitreous cavity) (Figure 1), exophytic

(towards the sub-retinal space) or diffusely infiltrative, causing placoid retinal thickness

rather than a discrete mass. Proptosis may be seen in advanced cases with orbital

extension. Atypical presentations include phthisis bulbi, vitreous haemorrhage, and

pseudohypopyon.22

Grouping & Staging

Grouping of RB is a clinical system to prognosticate the likelihood of ocular

salvage; staging is used to estimate the likelihood of survival. The Resse-Ellsworth

classification was introduced prior to the use of indirect ophthalmoscopy; it applies to

patients treated by means other than enucleation, and its components are

complicated.23 The more recently-developed International Classification of Intraocular

Retinoblastoma (ICIOR) scheme correlates grading with current treatment modalities

and is preferred. Two versions of that system are available.24,25 The TNM staging

scheme, developed by the American Joint Committee on Cancer (AJCC) and Union

Internationale Contre le Cancer (UICC), includes clinical and histopathological data

(Table 1).
 Delhiwala et al. Page 6

Histopathology of Retinoblastoma

Retinoblastoma is thought to arise from totipotential blasts in the retina.

Microscopically, it is usually characterized by alternating necrotic and viable areas. As

true of other small round-cell tumors, the neoplastic elements in retinoblastoma contain

only scanty cytoplasm and have deeply basophilic nuclei that show molding on one

another (Figure 2). Because retinoblastoma commonly outgrows it blood supply,

perivascular pseudorosettes and zonal necrosis are frequently seen. Flexner-

Wintersteiner and Homer-Wright rosettes (Figures 3 & 4) are present in differentiated

tumors, but glial differentiation is rare.

Pitfalls in Diagnosis

For the accurate detection of invasive features, it is important that both central

and peripheral calottes of the eyeball should be sampled. Peripheral foci of choroidal,

scleral, or extraocular invasion (Figures 5 & 6) may be missed if only a central calotte is

examined. Invasion of tumor cells into the choroid may cause them to be compressed,

resembling lymphocytes. Immunostaining for CD45 will resolve any confusion on that

point. Destruction of optic nerve axons by the tumor also can cause secondary

astrocytic proliferation, resulting in a misdiagnosis of true optic nerve invasion by RB

(Figure 7).

Effects of Irradiation or Chemotherapy

After successful responses to therapy, retinoblastoma may appear as amorphous

debris in a glial network. Relapsed lesions seen after treatment may be retinocytoma-

like histologically,sometimes with internal fleurettes.

 Delhiwala et al. Page 7

High Risk Factors (HRFs)

Clinical HRFs

Older age at presentation, hyphema, pseudohypopyon, orbital cellulitis,

staphyloma, elevated intraocular pressure, buphthalmos, and delayed enucleation after

diagnosis are associated with a poor prognosis.26-28 Modification of staging data,

especially regarding extraocular extension, by neoadjuvant chemotherapy may result in

inappropriately non-aggressive subsequent management according to a recent study.27

Histopathologic HRFs

Extraretinal extension (ERE) may still be seen in retinoblastoma cases. In

developing countries, up to 50% of affected eyes show ERE.29,30 This finding includes

spread of tumor to the choroid, iris &ciliary body, anterior chamber, sclera, and optic

nerve. Optic nerve involvement may be parenchymal or leptomeningeal.

The extent of uveal invasion correlates with the risk of extraocular relapse.31

Choroidal invasion may be focal (< 3 mm in any dimension) or massive (> 3 mm in any

dimension). The risk of extraocular disease in children with massive choroidal invasion

is 6%,32 and they have a lower probability of overall event-free survival as compared to

those with focal choroidal invasion.32 Pre-lamina cribrosa optic nerve invasion is not

associated with a significant risk of extraocular relapse. However, retrolaminar optic

nerve invasion is indeed a HRF and it necessitates the use of adjuvant chemotherapy.33

The risk is further increased when retrolaminar optic invasion is present along with

massive choroidal invasion or scleral compromise.34 Also, the concurrent presence of

focal choroidal invasion and pre-laminar optic nerve involvement is associated with a

greater risk of relapse than is either of those factors independently.35 Scleral invasion
 Delhiwala et al. Page 8

with neo-vascularization of the iris and neovascular glaucoma is likewise regarded as a

HRF.36

Recent Advances

In the recent past, the expression of several proteins has been studied in

retinoblastoma. High expression of high mobility group Box – 1 protein (HMGB1), polo-

like kinase-1 (PLK1), CDC25A, CDC25B, and bcl2, and the loss of mitochondrial

complex –1 have been linked to high histologic grade and invasiveness in RB.37-41 The

coexpression of bax and p53 is correlated with choroidal invasion.41,42 On the other

hand, a loss of mitochondrial complexes III, IV and V has been associated with better

survival.38

Differential Diagnosis

Clinical differential diagnoses for RB include Coats’ disease, toxocariasis,

persistent hyperplastic primary vitreous (PHPV), retinopathy of prematurity (ROP),

retinal dysplasia, and medulloepithelioma. Coats’ disease is the most frequently

encountered among those possibilities. Microscopically, it is characterized by

telangiectatic retinal vessels and lipid-rich sub-retinal exudates with numerous

macrophages (Figure 5). The histological diagnosis of retinoblastoma is usually

straightforward, especially with knowledge of the clinical findings and imaging studies.

It is appropriate to consider any intraocular, small round-cell tumor in a child under 5-

years of age as a retinoblastoma, unless proven otherwise. The diagnostic separation of

poorly differentiated forms of medulloepithelioma and retinoblastoma is difficult, and no

immunostains can distinguish between them. Moreover, although retinoblastomas are

typically posterior in location and medulloepitheliomas are anterior, the converse of that
 Delhiwala et al. Page 9

localization has been reported.43,44 Other histological diagnostic considerations include

rhabdomyosarcoma, leukemia, lymphoma, Ewing sarcoma/primitive neuroectodermal

tumor (PNET), and neuroblastoma. An immunohistochemical panel comprising CD45,

myeloperoxidase, CD34, CD43, CD117, desmin, myogenin, CD99, and FLI1 is useful in

that context.

Secondary Malignancies

Children with retinoblastoma, especially the hereditary form, have a significantly

risk of developing another malignancy later in life.45,46 It increases from 5% in the first

10 years after diagnosis to 44% at 45 years of age.45,46 Although the cumulative

incidence of a secondary malignancy is 35% in children who are irradiated, it is only 6%

in those who are not.46 Osteosarcoma is the commonest secondary tumor in those

children, but other reported lesions include rhabdomyosarcoma, neuroblastoma,

chondrosarcoma, leukemia, sebaceous carcinoma, squamous cell carcinoma, and

malignant melanoma.46 One study also reported a heightened incidence of secondary

acute myelogenous leukemia in patients with RB who were treated with topoisomerase

II inhibitors.47
 Delhiwala et al. Page 10

Treatment

The primary goal of treatment in patients with retinoblastoma is the preservation

of life; ocular salvage and preservation of vision are secondary. Management depends

on the age at diagnosis, tumor location, staging, overall patient fitness, and cost-

effectiveness of the therapeutic regimen. A multidisciplinary approach is best, involving

the ophthalmologist, oncologist, radiation physicist, pathologist, and ocularist.

Small equatorial and peripheral tumors up to 4 mm in basal diameter and 2 mm

in thickness are treated with cryotherapy.8,22 Posterior tumors of similar dimensions are

managedwith photocoagulation.8,22 Plaque brachytherapy, using ruthenium 106 and

iodine 125, is reserved for tumors up to16 mm in basal diameter and 8 mm in thickness.

With recent advances in chemotherapy, external radiotherapy is now used infrequently.

Advanced retinoblastomas are treated with enucleation followed by chemotherapy, if

HRFs are present.

Conclusions

Retinoblastoma is an aggressive but curable intraocular tumor, and its overall

management has included dramatic changes in recent years. The pathologist plays a

key role in management by careful assessment for histopathologic HRFs in enucleated

eyes.
 Delhiwala et al. Page 11

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Figure Legends

Figure 1: Ophthalmoscopic (left) and gross-pathologic (right) images of retinoblastoma.

Figure 2: Retinoblastoma of the left eye in a young child, producing proptosis (left); leukocoria

was also evident. Histologically, the mass comprises a small round-cell neoplasm with foci of

dystrophic calcification (right).

Figure 3: The microscopic formation of rosettes is evident in this retinoblastoma.

Figure 4: Flexner-Wintersteiner rosettes in a retinoblastoma.

Figure 5: Scleral invasion by retinoblastoma is shown here.

Figure 6: Invasion of the choroid (left) and ciliary body (right) is present in this example of

retinoblastoma.

Figure 7: Invasion of the optic nerve by retinoblastoma.

 Delhiwala et al. Page 15

Table 1: AJCC –TNM staging system for retinoblastoma

Primary Tumor (pT )

pTX Primary tumor cannot be assessed
pT0 No evidence of primary tumor
pT1 Tumor confi ned to eye with no optic nerve or choroidal invasion
pT2 Tumor with minimal optic nerve and/or choroidal invasion:
pT2a Tumor superfi cially invades optic nerve head but does not extend past lamina
cribrosa or tumor exhibits focal choroidal invasion
pT2b Tumor superfi cially invades optic nerve head but does not extend past lamina
cribrosa and exhibits
focal choroidal invasion
pT3 Tumor with signifi cant optic nerve and/or choroidal invasion:
pT3a Tumor invades optic nerve past lamina cribrosa but not to surgical resection line
or tumor exhibits
massive choroidal invasion
pT3b Tumor invades optic nerve past lamina cribrosa but not to surgical resection line
and exhibits
massive choroidal invasion
pT4 Tumor invades optic nerve to resection line or exhibits extra-ocular extension
elsewhere
pT4a Tumor invades optic nerve to resection line but no extra-ocular extension identifi
ed
pT4b Tumor invades optic nerve to resection line and extra-ocular extension identified

Regional Lymph Nodes (pN )

pNX Regional lymph nodes cannot be assessed
pN0 No regional lymph node involvement
pN1 Regional lymph node involvement (preauricular, cervical)
N2 Distant lymph node involvement

Metastasis (pM )
cM0 No metastasis
pM1 Metastasis to sites other than CNS
pM1a Single lesion
pM1b Multiple lesions
pM1c CNS metastasis
pM1d Discrete mass(es) without leptomeningeal and/or CSF involvement
pM1e Leptomeningeal and/or CSF involvement
Delhiwala et al. Page 16
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