2014, Volume 30, Number 3, Page(s) 171-177
A Histopathologic Analysis of 50 Eyes Primarily Enucleated for Retinoblastoma in a Tertiary Cancer Center in Jordan
Yacoub A YOUSEF1, Yasmin HAJJA1, Ibrahim NAWAISEH1, Mustafa MEHYAR1, Iyad SULTAN2, Rasha DEEBAJAH2, Khalil RAWASHDEH1, Samer KHURMA1, Imad JARADAT3, Maysa AL-HUSSAINI4
1Department of Surgery, King Hussein Cancer Center, AMMAN, JORDAN
2Department of Pediatrics, King Hussein Cancer Center, AMMAN, JORDAN
3Department of Radiotherapy, King Hussein Cancer Center, AMMAN, JORDAN
4Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, AMMAN, JORDAN
Keywords: Choroid, Optic nerve, Retinoblastoma, Eye
To analyze the histopathologic features of the eyes with
intraocular retinoblastoma primarily treated by enucleation in a
tertiary cancer center in Jordan.
Material and Method: A retrospective case series of 50 eyes for
49 patients who had pathologically confirmed retinoblastoma
after enucleation as primary therapy. The main outcome measures
included demographics, laterality, international classification of
intraocular retinoblastoma, choroid invasion, optic nerve invasion,
anterior chamber invasion, and tumor differentiation.
Results: The median age at enucleation was 30 months. Twenty-seven
(55%) patients were males, and 19 (39%) patients had bilateral
retinoblastoma. High risk pathological features were seen as massive
choroid invasion in 9 (18%) eyes, post-laminar optic nerve invasion
in 7 (14%) eyes, and anterior chamber, iris or ciliary body invasion
in 7 (14%) eyes. Thirty-seven (74%) tumors were well/moderately
differentiated, and 13 (26%) were poorly differentiated. Poorly
differentiated tumors presented later (median 31 months) than well/
moderately differentiated tumors (26 months) and were associated
with a higher incidence of high-risk pathological features. No single
ICRB group C eye had high-risk pathological features, while 17% and
4% of group D eyes and 28% and 33% of group E eyes had massive
choroid invasion and post-laminar optic nerve invasion, respectively.
Eighteen (36%) patients received adjuvant chemotherapy for high
risk pathological features, and at median follow up of 40 months, no
single case had metastasis or was dead.
Conclusion: Our pathologic findings were similar to the developed
world. They were supportive of the predictive power of the
international classification of retinoblastoma staging system for the
likelihood of high risk pathological features. Poorly differentiated
tumors were associated with a higher incidence of high risk
pathological features than well/moderately differentiated tumors.
Retinoblastoma (RB), a rare tumor arising from the inner
nuclear layer of the retina, is the most common primary
intraocular malignancy in childhood and infancy. The
incidence is estimated at about 1 in 15,000 to 20,000 live
The International Classification of RB (ICRB)5 emerged
in 2005, and staged RB according to tumor size and the
presence and extent of tumor seeding (Table I). ICRB staging
has been shown to assist in predicting those who are likely
to be cured by chemoreduction and focal therapy. With the
multidisciplinary therapeutic approach (chemotherapy,
thermal therapy, cryotherapy, and radiotherapy), ocular salvage is possible in group A through D intraocular tumors5. However, in group E tumors (and group D in unilateral
cases), enucleation remains the modality of choice5-8.
Some histopathologic findings in enucleated eyes,
designated as high-risk pathologic features (HRF), are
associated with a higher risk of local recurrence and distant
metastasis, and therefore need additional treatments such
as adjuvant chemotherapy and external beam radiation.
These HRF, which have been described, and debated, in the
literature include tumor invasion of the anterior chamber,
iris, ciliary body, massive choroid (more than 3 mm), sclera,
post-laminar portion of the optic nerve, combination of
focal choroid invasion (less than 3 mm) and optic nerve
invasion, as well as extra-ocular tumor extension9-15.
There are few studies that have evaluated HRF in eyes
enucleated for advanced intraocular retinoblastoma from
the developing world generally and from the Middle-
East specifically. Most of these reported higher incidences
compared with studies reported from the developed World15-21.
Herein, we report the results of a retrospective
histopathologic analysis of eyes primarily enucleated
for intraocular retinoblastoma at the single center for
management of retinoblastoma in Jordan; one of the
developing countries in the Middle East.
This study was approved by the Institutional Review Board.
It was a retrospective case series of 50 eyes of 49 consecutive
patients from January 2006 to November 2013 who had a
clinical diagnosis of intraocular retinoblastoma, which
was confirmed pathologically after primary enucleation.
Selection required access to patients' medical and pathologic
records. Pathology slides were reviewed when needed.
Data included patient's age, gender, laterality, age at
enucleation, follow up period, initial international
classification of retinoblastoma (ICRB) group5, presence
of choroid invasion (focal versus massive), level of optic
nerve invasion, anterior chamber invasion, scleral and
extra-scleral extension, tumor differentiation, metastasis,
Inclusion and Exclusion Criteria: The eligibility criteria for
inclusion were eyes with pathologic diagnosis of intraocular
retinoblastoma treated initially by enucleation without
receiving any focal therapy, chemotherapy or radiation
therapy. Exclusion criteria included eyes that received
any modality of treatment (focal therapy, chemotherapy,
radiation therapy) before enucleation. In this series, enucleation was considered the first line treatment for all
IRCB group E eyes, for unilateral ICRB group D eyes, and
for unilateral ICRB group C eyes with poor visual prognosis.
Table I shows rational of the ICRB staging system5.
Pathological Characteristics and Definitions: In this
study, high risk pathologic features included massive
choroid invasion, invasion of the post-laminar optic nerve,
invasion of optic nerve resection line, scleral infiltration
and anterior chamber invasion (iris infiltration, ciliary
body infiltration) by tumor cells.
Choroid invasion was defined as one or more solid nests of
tumor cells that fills or replaces the choroid and has pushing/
infiltrative borders. Tumors were divided into three groups;
1. No choroid invasion, 2. Focal choroid invasion: (less
than 3 mm in the maximum diameter (width or thickness)
and without touching the sclera), and 3. Massive choroid
invasion (solid tumor nest 3 mm or more in maximum
diameter; width or thickness and touches the inner surface
of the sclera). Extent of optic nerve invasion was divided
into three groups; 1. No optic nerve invasion, 2. Laminar or
pre-laminar optic nerve invasion, and 3. Post-laminar optic
Tumors were divided into 2 groups according to level of
differentiation; 1. Well/moderately differentiated tumors
(defined as tumors composed of small round blue cells, but
show features of differentiation in the form of fluerettes,
Flexner-Wintersteiner or Homer-Wright rosettes), and 2.
Poorly differentiated tumors (defined as tumors composed
of small round blue cell tumors that lacked any evidence of
Endophytic tumor was defined as tumor that grows towards
the vitreous cavity, and exophytic tumor was defined as
tumor that grows outwards between the sensory retina
and retinal pigment epithelium. When both patterns exist
together, the growth pattern considered as combined.
In our center, indications for adjuvant chemotherapy after
enucleation included optic nerve involvement posterior to
the lamina cribrosa, massive choroid invasion, any degree of
concomitant choroid and optic nerve involvement, anterior
chamber seeding, ciliary body infiltration, iris infiltration,
and scleral invasion
Between January 2006 and November 2013, 50 eyes for 49
patients underwent enucleation as primary treatment for
Demographics and Clinical Features: There were 27 males
(55%) and 22 females (45%). There were 30 (61%) unilateral
and 19 (39%) bilateral cases. One patient had bilateral
enucleation as primary treatment. The median age at time
of enucleation was 30 months (mean, 28 months; range,
5–61 months) for the whole group; 25 months (mean, 25
months; range, 5–50 months) for the unilateral cases and 31
months (mean, 33 months; range; 5 to 60 months) for the
bilateral cases (Table II).
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|Table II: Demographics and clinical features of 49 patients (50
eyes) primarily enucleated for retinoblastoma
According to the international intraocular retinoblastoma
classification (ICRB) (5); in this series, 8 (16%) eyes were
ICRB group C, 25 (50%) eyes were ICRB group D, 17 (34%)
eyes were ICRB group E, and no one eye was ICRB group A
or B (Table II). Neovascular glaucoma was seen in 14 (28%)
Pathologic Features: Seventeen eyes (34%) did not show
any element of choroid, optic nerve, scleral, ciliary body, or
anterior chamber invasion. Choroid invasion was seen in 22
(44%) eyes; 9 (18%) eyes had massive choroid invasion and
13 (26%) had focal choroid invasion. Optic nerve invasion
was seen in 23 (46%) eyes; 16 (32%) had laminar or prelaminar
optic nerve invasion and 7 (14%) eyes had post
laminar optic nerve invasion. Anterior chamber invasion
was seen in 7 (14%) eyes, 3 (6%) of them had ciliary body
invasion. No single eye in this series had scleral or extrascleral
tumor extension, and no one had tumor at the optic
nerve resection margin.
Endophytic growth pattern was seen in 21 (42%) eyes,
exophytic growth pattern was seen in 15 (30%) eyes,
and combined growth pattern was seen in 14 (28%) eyes
(Figure 1A-D). No one eye had diffused infiltrative growth
pattern. Thirty-seven (74%) of the tumors were well/
moderately differentiated while 13 (26%) eyes were poorly
differentiated. Out of the 37 well/ moderately differentiated
tumors, 14 (38%) eyes had choroid invasion and 16 (43%)
eyes had optic nerve invasion, while out of the 13 poorly
differentiated tumors, 8 (62%) eyes had choroid invasion
and 8 (62%) eyes had optic nerve invasion. The median
age at enucleation for the well/moderately differentiated
tumors was 26 month, while it was 31 months for the poorly
differentiated tumors (Table III).
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|Figure 1: Different
pathological features of
A) Endophytic tumor
growth pattern, with
tumor growing towards
the vitreous body away
from the choroid and sclera
B) Exophytic tumor growth
pattern associated with
(H&E, x200), C) Massive
choroid invasion defined
as invasion of the choroid
>3 mm in any dimension
(H&E, x400x), D) Postlamina
cribrosa optic nerve
invasion can be seen in
some eyes (H&E, x200).
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|Table III: Histopathologic findings in 50 eyes primarily
enucleated for retinoblastoma
Correlation Between International Classification and
Histopathology: According to the ICRB classification; 8
(16%) of eyes in this series were ICRB group C; one of the
tumors (13%) was poorly differentiated, 2 eyes (25%) had
choroid invasion (focal in both of them), and one eye (13%)
had pre-laminar optic nerve invasion. Twenty-four (48%) eyes
were ICRB group D; 2 (8%) tumors were poorly differentiated,
8(34%) had choroid invasion, 4 (17%) had massive choroid
invasion, and 11 (48%) had optic nerve invasion, only one
(4%) of which was post-laminar. Eighteen (36%) eyes were
ICRB group E; 10 (56%) tumors were poorly differentiated,
12 (67%) had choroid invasion, 5 (28%) had massive choroid
invasion, and 11 (61%) had optic nerve invasion, 6 (33%)
of which were post-laminar. Table IV summarizes the
correlation between the ICRB group and HRF.
Follow Up: The median follow up was 40 months (range;
3-100 months). Eighteen (36%) cases received adjuvant
chemotherapy; 11 (22%) for massive choroid invasion
and/or post-laminar optic nerve invasion, and 3(6%) for
concomitant focal choroid invasion and laminar optic
nerve invasion, 7 (14%) for anterior chamber, iris, or ciliary
body invasion (3 of them had concomitant massive choroid
or post-laminar optic nerve invasion). No single case in this
series received radiation therapy, and no single case had
metastasis or was dead at last date of follow up. No patients
were lost to follow-up.
In this series, we examined the histopathology of 50 eyes
primarily enucleated for retinoblastoma. Sixty-six percent
of the eyes in our series showed some element of choroid,
optic nerve, sclera, or anterior chamber tumor infiltration,
while only 36% of the eyes showed HRF, and accordingly
received adjuvant chemotherapy. No single eye received
radiation therapy, and all patients were alive with no
metastasis or orbital recurrence at a median follow-up of
In the study by Zhao et al.22, analysis of children with
advanced intra ocular retinoblastoma showed lower
disease-specific survival in those received pre-enucleation
chemotherapy, since pre-enucleation chemotherapy can
down-stage pathologic evidence of risk for extra-ocular
extension, and therefore inadequate management by not
receiving the needed adjuvant chemotherapy. In our series
we included the eyes primarily enucleated without receiving
pre-enucleation chemotherapy and thus the incidence of
HRF reported in our series could truly represent the risk
for metastasis. Similar to Zhao et al. results22, no single
case in our series (who did not receive pre-enucleation
chemotherapy) had metastasis.
Tumor's differentiation was highly variable between
different reports from the developing world. Many showed
higher incidence of poorly differentiated (up to 80%)
compared to well differentiated tumors, probably due to
late age of presentation15-17. Most tumors (74%) in our
series as well as tumors reported by Filho et al. (95%)23
were well or moderately differentiated.
In our study, and similar to results reported by Eagle
et al.24 and Madhavan et al.25, we observed that
irrespective of laterality, well/moderately differentiated
tumors presented earlier (median 26 months) than poorly
differentiated tumors (31 months). In addition, and similar
to results reported by Kashyap et al.15, we noticed that
poorly differentiated tumors were associated with higher incidence of HRF. These observations could be related
to tumor progression and dedifferentiation from less
aggressive, better differentiated tumors to more aggressive
poorly differentiated tumors, a phenomenon that is well
described in tumors in other organs like the thyroid gland
and the esophagus15,23-27.
The reported incidence of the various histopathologic
features in eyes enucleated for retinoblastoma is highly
variable, and generally the incidence of choroid and optic
nerve invasion in the developing world was higher than in
the developed world (Table IV)10,11,15,18,19,24,28-30.
The overall reported incidence of optic nerve involvement
beyond the lamina cribrosa and at the resection margin
ranged from 6.5% to 40%, while the overall reported
incidence of massive choroid invasion ranged from 12%
to 41%. In our series, 18% of eyes had massive choroid
invasion and 14% had post laminar optic nerve invasion,
which is comparable to the results reported from the
developed world, and is less than the results reported from
the developing world (Table V)10,11,15,18,19,24,28-30. The higher incidence of these risk factor in developing
world might be related to later presentation (more advanced
stage) in relation to the lower socioeconomic status and the
delay in getting the needed treatment.
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|Table V: Comparison of incidence (%) of choroid and optic nerve invasion in various reported series
The Clinical International Classification5 for intraocular
retinoblastoma emerged in order to predict tumor response
for chemotherapy, and of interest it was found to predict
the likelihood of HRF as well10. Wilson et al.10 in an
analysis of 67 eyes found that 50% of enucleated group E
eyes had HRF while only 15% of Group D eyes had HRF
(p=0.005). Similarly, in our series no single group C eye
had HRF, 17% and 4% of group D eyes and 28% and 33%
of group E eyes had massive choroid invasion and post
laminar optic nerve invasion, respectively.
In conclusion, this is a retrospective histopathologic
analysis of a 50 eyes treated by primary enucleation
without receiving any previous chemotherapy or focal
therapy. Although Jordan is a developing country, our
pathologic findings and the incidence of HRF were similar
to that reported in literature from the developed world.
One plausible explanation is the centralization of this
service to only a single referral tertiary center treating all
retinoblastoma cases. This has lead to decrease the delay in
diagnosis as well as getting an adequate management. Our
pathologic findings revealed a predictive value of the ICRB
staging system for the likelihood of HRF after enucleation
where the more advanced ICRB stage at diagnosis was
associated with higher incidence of HRF.
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