2015, Volume 31, Number 1, Page(s) 045-050
The Impact of Growth Patterns of Retinoblastoma (Endophytic, Exophytic, and Mixed Patterns)
Ibrahim NAWAISEH1, Maysa AL-HUSSAINI2, Aamer ALHAMWI3, Mustafa MEYAR1, Iyad SULTAN2, Khalil ALRAWASHDEH1, Imad JARADAT4, Yacoub A YOUSEF1
1Department of Surgery/Ophthalmology, King Hussein Cancer Center, AMMAN, JORDAN
2Department of Pathology, King Hussein Cancer Center, AMMAN, JORDAN
3Department of Pediatrics, King Hussein Cancer Center, AMMAN, JORDAN
4Department of Radiotherapy, King Hussein Cancer Center, AMMAN, JORDAN
Keywords: Choroid, Retinoblastoma, Eye, Prognosis
To study the impact of the retinoblastoma growth pattern
(endophytic vs. exophytic) on the clinical and pathological features
after primary enucleation.
Material and Method: A retrospective case series of 42 eyes of 41
patients who had pathologically confirmed retinoblastoma. The main
outcome measures included demographics, laterality, international
intraocular retinoblastoma (IIRC) group, vitreous seeding,
neovascular glaucoma, choroid invasion, optic nerve invasion,
metastasis, and survival.
Results: The median age at diagnosis was 30 months. Nineteen
(46%) patients were males, and 17(41%) patients had bilateral
retinoblastomas. Eight (19%) eyes were IIRC group C, 20 (48%) eyes
were IIRC group D, and 14 (33%) eyes were IIRC group E. Nineteen
(45%) tumors were endophytic, 14 (33%) were exophytic, and 9 (21%)
were mixed. Choroid invasion was seen in 4 (21%) of the endophytic
tumors, 5 (36%) of the exophytic tumors, and 8 (89%) of the mixed
tumors (p=0.025). A mixed growth pattern was associated with
massive choroid invasion in 5 (56%) of eyes. Neovascular glaucoma
was seen in 5 (56%) of the mixed tumors (p=0.0376). Vitreous seeds
were seen in 6 (67%) of the mixed tumors (p=0.0448). Optic nerve
invasion as well as patients' age at diagnosis, gender, and tumor
laterality had no correlation with tumor growth pattern. At a median
follow up of 36 months, no single case had metastasis or was dead.
Conclusion: Exophytic tumors have higher risk of choroid invasion,
while endophytic tumors have higher risk of vitreous seeding. The
mixed tumor growth pattern is associated with more advanced IIRC
group, more risk of neovascular glaucoma, and more risk of massive
Retinoblastoma, a rare tumor arising from the retina, is
the most common primary intraocular
childhood and infancy. The incidence is estimated at about
1 in 15,000 to 20,000 live births1-3
Retinoblastoma originates from the inner nuclear layer
of the retina4, and the clinical presentation is variable
according to the growth pattern of the tumor. The growth
pattern of retinoblastoma was divided into endophytic
and exophytic types more than 100 years ago5. Tumors
that grow towards the vitreous cavity are called endophytic
tumors, and they are visible clinically by ophthalmoscopy.
Endophytic tumors are usually observed as a white retinal
mass lesion surrounded by fine feeding vessels and
sometimes tumor seeds. On the other hand, tumors that grow
outwards between the sensory retina and retinal pigment
epithelium are called exophytic tumors, and usually present
as retinal detachment secondary to tumor that is invisible by
ophthalmoscopy. Exophytic tumors initially appear as small
grey masses that are difficult to identify. As a tumor grows,
retinal detachment will be progressive and may end up with
total retinal detachment4. Some retinoblastomas manifest
endophytic and exophytic growth patterns at the same
time (mixed endophytic-exophytic retinoblastoma). Only
1-2% of cases of retinoblastoma exhibit a diffuse infiltrating
growth pattern where the tumor grows diffusely within the
retina without the formation of a discrete mass6.
Diffuse infiltrating retinoblastomas are often misdiagnosed
as uveitis since they present with signs suggestive of
inflammation7. Endophytic retinoblastoma may be
misdiagnosed as astrocytic hamartoma, while exophytic
retinoblastoma when present with total retinal detachment
may be misdiagnosed as Coat’s disease, persistent
hyperplastic primary vitreous, retinopathy of prematurity,
and retinal dysplasia8,9.
Herein we studied the association between tumor growth
patterns (endophytic vs. exophytic) and the presence of
high-risk pathological features (HRF) after enucleation.
This study was approved by the Institutional Review Board.
It was a retrospective case series of 42 eyes of 41 consecutive
patients from January 2006 to December 2012 that had
a clinical diagnosis of intraocular retinoblastoma, which
was confirmed pathologically after enucleation. Selection
required access to patients’ medical and pathological records.
Data included patient’s age, gender, laterality, age at
diagnosis, initial international intraocular retinoblastoma classification (IIRC)10 group, presence of vitreous
seeds, choroid invasion (focal versus massive), optic nerve
invasion, metastasis, second malignancy and mortality.
Inclusion and exclusion criteria; The eligibility criteria
for inclusion were eyes with a pathological 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. All
eyes with extra ocular retinoblastoma were excluded.
Pathological Characteristics and definitions: An endophytic
tumor was defined as tumor that grows towards the vitreous
cavity, and an exophytic tumor was defined as a tumor that
grows outwards between the sensory retina and retinal
pigment epithelium. When both patterns existed together,
the growth pattern was considered as mixed.
Choroid invasion was defined as the presence of one
or more solid nests of tumor cells that fill or replace the
choroid and have pushing/infiltrative borders. Tumors were
divided into three groups; 1. No choroid invasion, 2. Focal
choroid invasion (less than 3 mm in maximum diameter,
width or thickness and not 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 prelaminar optic
nerve invasion and 3. Retrolaminar optic nerve invasion.
Statistical Analysis; Statistical analysis of tumor growth
patterns were correlated to the gender, laterality, IIRC
group, presence of vitreous seeds, presence of neo-vascular
glaucoma, choroid invasion, and optic nerve invasion. The
P value was measured using the exact Fisher test to test the
predictive power of each factor.
Between January 2006 and December 2012, there were 42
eyes of 41 patients with intraocular retinoblastoma (IIRC
group C, D, or E) treated by primary enucleation.
Demographics; The mean age at time of enucleation was 30
months (median, 29 months; range, 5–61 months). There
were 19 males (46%) and 22 females (54%). There were 24
(59%) unilateral and 17 (41%) bilateral cases. The median
follow up was 36 months (range; 12-90 months). The
impact of patients’ demographics on tumor growth pattern
is presented in Table I.
Tumor features: Of the 42 eyes in this series, 8 (19%)
eyes were IIRC group C, 20 (48%) eyes were IIRC group
D, and 14 (33%) eyes were IIRC group E. An endophytic
growth pattern was seen in 19 (45%) eyes, an exophytic
growth pattern was seen in 14 (33%) eyes, and an mixed
growth pattern was seen in 9 (21%) eyes (Figure 1A-E).
An infiltrative growth pattern was not reported in any
eye. Seven (88%) of IIRC group C eyes were endophytic,
1 (13%) was exophytic, and none was of the mixed type.
Seven (35%) of IIRC group D eyes were endophytic, 10
(50%) were exophytic, and 3 (15%) were of the mixed type.
Five (36%) of IIRC group E eyes were endophytic, 3 (21%)
were exophytic, and 6 (43%) were of the mixed type (Table
I). The mixed growth pattern was significantly associated
with more advanced IIRC group (p=0.0407).
Click Here to Zoom
|Figure 1: Different patterns of
retinoblastoma growth. A) Exophytic
growth pattern associated with (H&E;
x200), B) Massive choroidal invasion
defined as invasion of the choroid >3mm
in any dimension (H&E; x400). C; postlamina
cribrosa optic nerve invasion can
be seen as well (H&E; x200).
D) Endophytic growth pattern, with
tumor growing towards the vitreous body
away from choroid and sclera (H&E; x40).
E) Mixed growth pattern, where part of
the tumor is growing towards the vitreous
(red arrow) and part is invading the
choroid (black arrow) (H&E; x40).
The impact of growth pattern on pathological features;
Choroid invasion was seen in 17 (40%) eyes; 4 (21%) of
endophytic tumors, 5 (36%) of exophytic tumors, and 8
(89%) of mixed tumors. An exophytic component was
significantly associated with higher risk of choroidal
invasion (p=0.0252). Focal choroidal invasion was seen in
11 (26%) eyes, and massive choroidal invasion was seen in
6 (14%) eyes. There was no single case of endophytic tumor
associated with massive choroidal invasion, while a mixed
growth pattern was associated with massive choroidal
invasion in 5 (56%) eyes with statistical significance
(p=0.0498) (Table II).
Optic nerve invasion was seen in 17 (40%) eyes; 8 (42%) of
the endophytic tumors, 4 (29%) of the exophytic tumors,
and 5 (56%) of the mixed tumors, with no statistical
significance (p=0.321). Of note, 2 (11%) of the endophytic
tumors, and 3(33%) of the mixed tumors had post-laminar optic nerve invasion while no single exophytic tumor had
post-laminar optic nerve invasion (Table II).
A clinical diagnosis of neovascular glaucoma was made
in 3 (16%) of the endophytic tumors, 3 (21%) of the
exophytic tumors, and 5 (56%) of the mixed tumors.
Tumors with a mixed growth pattern were at higher risk
to develop neovascular glaucoma than non-mixed tumors
(p=0.0376). Vitreous seeds were seen in 14 (74%) of the
endophytic tumors, 5 (36%) of the exophytic tumors, and 6
(67%) of the mixed tumors. Vitreous seeds were seen more
commonly with endophytic tumors or tumors with an
endophytic growth component than with exophytic tumors
(p=0.0448). Patients’ gender, age, and tumor laterality were
not associated with significant difference in the growth
pattern of the tumor (Table II). All patients with high-risk
pathological features received adjuvant chemotherapy. No
single case had metastasis or was dead at the last date of
Some histopathological findings in enucleated eyes with
retinoblastoma, designated as high-risk pathologic features,
are associated with a higher risk of tumor metastasis, and
therefore need additional treatment such as adjuvant
chemotherapy. These high-risk features include massive
choroid invasion, post-laminar invasion of the optic nerve,
invasion of the optic resection margin, and tumor invasion
of the anterior chamber, iris, cilliary body, sclera, as well as
extra-ocular tumor extension11-16
Endophytic tumors grow towards the vitreous cavity and
present as a vascular intraocular mass, while exophytic
tumors grow between the retina and the retinal pigment epithelium and therefore usually present with retinal
detachment. Our analysis of endophytic and exophytic
growth patterns in eyes with pathological diagnosis of
retinoblastoma that had no treatment before enucleation
showed that an exophytic component of the tumor is
associated with higher risk of choroidal invasion, while an
endophytic tumor component is associated with higher risk
of vitreous seeding. A mixed growth pattern of the tumor
was associated with more advanced IIRC group, more risk of
neovascular glaucoma, and more risk of massive choroidal
invasion. Optic nerve invasion as well as patients’ age at
diagnosis, gender, and tumor laterality had no correlation
with the tumor growth pattern.
Reese5 stated that endophytic tumors are more common
than exophytic tumors in 1976. In 1990 Palazzi et al.4
analyzed 297 retinoblastomas and classified them into
either endophytic or exophytic and showed that 61% were
endophytic and 39% were exophytic tumors. Similarly our series showed that endophytic tumors are more common
than exophytic tumors; 45% of our cases were endophytic,
33% were exophytic, and 21% had a mixed growth pattern.
No single case in our series had the diffuse infiltrating
growth pattern type, which is the rarest of all patterns.
Taktikos17 reported a diffuse infiltrating type in 1% of
Exophytic tumors grow towards the choroid and are
expected to have higher risk of choroidal invasion than the
endophytic type since the latter grows towards the vitreous
and away from the choroid. Palazzi et al.4 supported
this theory by finding that 71% of tumors with choroidal
invasion had an exophytic growth pattern. In this series we
supported this finding and were able to show that massive
choroidal invasion, as defined recently, was more likely to
occur in tumors with an exophytic growth pattern, while
not a single case of endophytic tumor had massive choroidal
invasion. On the other hand, optic nerve invasion did not correlate with tumor growth pattern in this series, similar to
what was shown by Palazzi et al.4 in their analysis of 297
cases. On the contrary, endophytic tumors were more likely
to be associated with vitreous seeds than the exophytic type,
probably due to the fact that direct contact of the tumor
with the vitreous (no inner retinal border) makes it easier
for few cells to escape the surface of the tumor and to invade
Wilson et al.11 and Kaliki et al.12 showed a higher
incidence of high-risk features in Reese-Ellsworth (RE)18 group Vb eyes (eyes with vitreous seeds) than group
Va eyes (eyes without vitreous seeds); Wilson et al.11
showed that group Vb eyes (eyes with vitreous seeds) were
associated with a 58% risk of optic nerve invasion (laminar
or post laminar), and only 29% risk of massive choroid
invasion, and since our study showed that vitreous seeds
were significantly more likely to be associated with an endophytic growth pattern (Table II), we can conclude that
endophytic tumors are more likely to be associated with
optic nerve invasion than choroid invasion.
A mixed tumor growth pattern was indicative of a more
advanced tumor stage, and a long-standing damaging
tumor. In this series, the mixed growth type was significantly
associated with more advanced IIRC group, where 67% of
the mixed tumors were IIRC group E, the most advanced
stage of intraocular retinoblastoma. Similarly neovascular
glaucoma was significantly seen more commonly with the
mixed tumor type (p=0.0376). Palazzi et al.4 showed a
higher risk of glaucoma in exophytic type that might be due
to ischemia secondary to long-standing retinal detachment,
but in that series they divided the tumors into either
endophytic or exophytic without evaluating the impact of
the mixed growth pattern on their cases.
Of interest, not a single case in our series had metastasis
although one third was IIRC group E, and none of them
had chemotherapy before enucleation. This is consistent
with Zhao’s et al.19 findings who recently found that
chemotherapy before enucleation in group E eyes can
downstage pathologic evidence of extraocular extension,
and therefore increase the risk of metastatic death from
reduced surveillance and inappropriate management
of high-risk disease, and similar to our results, none
of their patients who had primary enucleation without
chemotherapy had metastasis19.
This study examined the impact of retinoblastoma growth
pattern on clinical and pathological features. Although this
is a unique work, it is retrospective and of a limited size.
Therefore, a larger and more comprehensive multicenter
study needs to be performed to better analyze the impact
of tumor growth pattern on the clinical and pathological
features of the tumor, which may add to our understanding
this rare life-threatening disease.
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