Clinical epidemiology of retinoblastoma at the Philippine General Hospital: 1998-2008
- Sharlene I. Noguera, MD
Gary John V. Mercado, MD
Darby E. Santiago, MDDepartment of Ophthalmology and
Visual Sciences
University of the Philippines–
Philippine General Hospital
Manila, Philippines
RETINOBLASTOMA (RB) is the most common
primary intraocular malignancy of childhood, accounting
for around 4% of all pediatric malignancies.1-2 It is
a highly malignant tumor of the eye that manifests most
often in the first 3 years of life.3 About 250 to 300 new
cases of RB are diagnosed in the United States each year
and 5,000 worldwide.4
Leukocoria (cat’s eye reflex) and strabismus are the
most common presenting signs or symptoms of RB,5-6 reported
in both local and international studies. Metastasis
generally develops within 1 year of the diagnosis of the
intraocular tumor. Risk factors include invasion beyond
the lamina cribrosa onto the optic nerve, choroid (>2 mm
dimension), sclera, orbit, and anterior chamber. Invasion
of the optic nerve or choroid generally involves a large
RB tumor, over 15 millimeters at its greatest dimension,
along with elevated intraocular pressure and total retinal
detachment.7
Because RB is highly malignant and the mortality
rate reaches 99% if left untreated, the primary goal of
management is patient survival. Preservation of the
globe and visual acuity are secondary goals. In the 1960s
when external beam radiotherapy (EBRT) was the most
popular conservative (non-enucleation) treatment,
Reese–Ellsworth classification based on location, multifocality,
and size of the tumor was created.8 At that time,
peripheral RBs at the ora serrata, multifocal tumors, and
larger tumors were more difficult to treat than smaller,
single, macular tumors. Hence, peripheral, multifocal,
and large tumors were assumed to be more aggressive
and earned a higher ranking in the Reese–Ellsworth classification,
implying a worse ocular prognosis.
In the mid-1990s, there was a gradual shift in conservative
treatment methods for retinoblastoma from EBRT to
CRD (combined with focal therapies).The limiting factors
for RB control in the CRD era were different than in the
EBRT era and related predominantly to the management
of associated vitreous and subretinal seeds. The problem
of subretinal seeding and differentiation between focal
and diffuse vitreous seeding was not addressed in the
Reese–Ellsworth classification. For these reasons, it was
found to be a poor predictor of CRD success.9
The International Classification of Retinoblastoma
(ICRB) was formulated based mainly on extent of tumor
seeding in the vitreous cavity and subretinal space with
minor consideration of tumor size and location.9 It was
intended to predict globe outcome and has shown to be
predictive after CRD. Patients within groups A, B, and
C had considerable chances for globe salvage and avoidance
of EBRT. Patients within group D had much lower
chance of success, with approximately one half requiring
EBRT or enucleation.10
Unilateral RB is generally managed with enucleation
if the eye is classified as Reese-Ellsworth group V, and
chemoreduction or focal measures are intended for
groups I-IV. In bilateral RBs, chemoreduction is required
in most cases unless there is extreme asymmetric involvement,
with one eye having advanced disease necessitating
enucleation and the other minimal disease treatable with
focal methods.1-2, 10
In a local study, Espiritu et al. noted that the epidemiological
and clinical patterns of retinoblastoma cases
seen at the University of the Philippines–Philippine General
Hospital (UP–PGH) may be changing over time
and required continuous monitoring of incidence and
characteristics.11
The UP–PGH is a tertiary government hospital that
receives most retinoblastoma referrals in the Philippines.
These cases were initially seen by the retina service
of the Department of Ophthalmology. In 1997, the
Retinoblastoma-Ocular Oncology Unit was established
and handled all these referrals. With the vast number of
clinical records available at the unit, the demographics
and clinical characteristics of retinoblastoma cases in the
last decade can be studied.
Thus, this study determined the clinical characteristics
of RB cases seen at UP–PGH from 1998 to 2008 and compared
them with local data from previous decades (1967
to 2001) and other centers. It determined the changes in
trends in terms of demographics, time of consultation,
treatment parameters, and other clinical characteristics.
METHODOLOGY
This study is a retrospective review of medical records of all patients diagnosed with RB between 1998 and 2008 at the UP–PGH Retinoblastoma Clinic. Each chart was assigned a number to keep the name of the patient confidential. Demographic data collected included age at first symptom/sign, age at diagnosis, sex, family history of RB, age at first treatment, lag period between first symptom/ sign and diagnosis, and lag period between diagnosis and treatment. Ophthalmological data collected consisted of visual acuity, laterality, and clinical staging. Data were recorded in Microsoft Excel (Microsoft Corporation, Redmond, WA, USA) and analyzed using SPSS for Windows. Patients with unilateral and bilateral RBs were compared. T-test for equality of means was used with a p value of <0.05 considered significant. The data gathered were also compared with earlier local data.
RESULTS
RB patients included 78 males and 74 females, with a
mean age of 24.2 ± 14.2 months at initial consultation.
Ninety-five (62.5%) of the 152 patients had unilateral
tumor while 57 (37.5%) had bilateral tumors. Of the
patients with bilateral tumors, 25 (43.9%) sought consultation for symptoms/signs in both eyes, while 32 (56.1%)
sought consultation for one eye but were found to have
bilateral RBs. One patient presented with a unilateral
tumor at age 1.5 months and developed RB lesions in
the fellow eye after 4 months. Three patients with unilateral
and 7 with bilateral RBs had a family history of RB
(p = 0.03). Among those with unilateral RB, the mean
age at initial symptom/sign was 17.8 months, which was
significantly older than in the bilateral group (p < 0.001).
The mean age at diagnosis was 26.4 months in those with
unilateral and 13.7 months in those with bilateral RBs (p
< 0.001). The mean lag time from discovery of initial sign
or symptom to diagnosis was 9.1 for the unilateral and
5.9 months for the bilateral groups (p = 0.03). Sixty-six
(69%) with unilateral RB and 32 (56%) with bilateral
RBs consulted late (Table 1).
Table 1. Characteristics of children diagnosed with retinoblastoma
from 1998 to 2008.
Delay from Onset to Diagnosis
The delay from initial sign or symptom to diagnosis
of less than 1 month was 3.2% (3/95) of the unilateral
and 21.1% (12/57) of the bilateral RB groups; delay of
1 to 3 months was 24.2% (23/95) of the unilateral and
28.1% (16/57) for the bilateral groups; delay of greater
than 3 months was 72.6% (69/95) of the unilateral and
50.9% (29/57) of the bilateral groups. The bilateral
group significantly presented earlier compared with the
unilateral group.
Combining both unilateral and bilateral groups, 9.9%
(15 of 152) had a delay from initial symptom to diagnosis
for less than a month; 25.7% (39 of 152) had a delaybetween 1 to 3 months; and 64.5% (98 of 152 patients)
had a delay in consultation of greater than 3 months.
Financial cost (71.4%) was the leading reason for the
delay from initial symptom to diagnosis, followed by
misdiagnosis (24.5%) and inaccessibility of medical facility
(2%). In 1% of cases, the reasons were not indicated,
while in another 1% the patients were initially treated
with herbal medications.
The most common misdiagnoses for RB were congenital
cataract (25%) and eye infections (25%). Other
misdiagnoses were uveitis/uveitic cataract (15%), glaucoma
(15%), posttraumatic cataract (5%), strabismus
(5%), blind eye (5%) and vitamin-A deficiency (5%).
One patient was misdiagnosed to have glaucoma and
underwent glaucoma surgery. Intraoperatively, an
intraocular mass was noted. Most patients were initially
seen by their local ophthalmologists (except for patients
with vitamin-A deficiency who were seen by a general
practitioner).
Most of the patients were from Metro Manila (28.9%),
followed by provinces around Metro Manila such as
Laguna (7.2%), Bulacan (5.3%), Cavite (3.9%), and Rizal
(3.3%).
Age at Consultation
The mean age at initial diagnosis was 26.43 months
for unilateral and 13.66 months for the bilateral RB
groups (p < 0.001). The parents of 12 patients (6 in
each group) refused treatment; these patients had no
follow-up. The mean lag time between the diagnosis
and first treatment was 1.1 months for the unilateral
and 1 month for the bilateral groups (p = 0.66). Treatment
was delayed for 14 months in 1 patient due to the
parent’s initial refusal. RB was in the advanced stage in
the right eye (stage VB, E) and extraocular stage in the
left; both eyes were eventually enucleated. After one
cycle of chemotherapy, the tumor recurred 1 month
postoperatively in the left eye and the patient was lost
to follow-up.
Presenting Sign
Leukocoria was the presenting sign in 117 (77%)
patients, followed by orbital mass (14), proptosis (6), and
strabismus (4). Poor vision at presentation (defined as
no dazzle, no light perception) was found in 91 (95.8%)
patients with unilateral tumor. The other 4 patients had
at least dazzle on visual examination. Among those with
bilateral tumors, 15 (26.3%) presented with poor vision
in both eyes, while 38 (66.7%) presented with poor vision
in the worse and good vision (defined as with at least
dazzle; central, steady and maintained; and finger play)
in the better eye. Only three (5%) presented with good
vision in both eyes.
Clinical staging
Tables 2 and 3 summarize the clinical staging at
diagnosis according to the Reese–Ellsworth Classification
and the ICRB. In the Reese-Ellsworth Classification, the
most common stage was V-B; 71.6% in those with unilateral
and 60% (34 for each eye) in those with bilateral
tumors. The unilateral group presented at stage IV-A and
higher while the bilateral group presented at varying
stages. Among those with bilateral RBs, one eye usually
presented in an advanced stage and the other at a lower
stage or were incidentally found to have RBs at consultation.
The same pattern was seen in the ICRB staging. The
unilateral group presented at stage D and higher, while
the bilateral group presented at all stages. Sixty-three
percent (66) in the unilateral and 56% (32 for each eye)
in the bilateral groups presented with stage E.
DISCUSSION
This study recorded 152 RB cases at the UP–PGH from
1998 to 2008. Similar retrospective studies reported 96
cases in Taiwan from 1978 to 2000, 90 in Thailand from
1997 to 2006, 141 in Turkey from 1981 to 2004, and 142
in Australia from 1974 to 2005.13-16 Of the 152 cases,
62.5% were unilateral and 37.5% were bilateral, similar
to those reported. Of the bilateral cases, 56.1% consulted
for unilateral signs/symptoms but were found to have
bilateral disease. One patient was initially diagnosed to
have unilateral disease but developed tumor in the fellow
eye after 4 months of monitoring. Thus, it is important
to examine and monitor both eyes in apparent unilateral
cases.
Similar to previous reports, bilateral cases manifested
earlier than unilateral cases. There was a ten-month difference
in age of onset between unilateral and bilateral
cases, although there was no significant change in the
age of onset compared with earlier local studies. The
mean age of presentation was 18 months for unilateral
and 8 months for bilateral RBs, suggesting that patients
found to have signs and symptoms before age 12 months
should be suspected of bilateral disease.
The percentage of familial incidence has not increased
compared to data from previous years.5,11-17 In this study,
the familial incidence was 3% for the unilateral and
7% for the bilateral groups. No gender predilection
was found, consistent with local and international
reports.5,11-17
Consistent with previous reports,5,11-17 the most common
presenting sign was leukocoria. Signs suggestive of
extraocular extension such as proptosis declined from
16% in 1967 to 197711 to 6% in 1985 to 1995,11 while
findings of orbital mass dropped from 27% to 11%.11 In
this study, there was a slight increase in the number of patients
who presented with proptosis (Figure 1). Although 64.5% of patients had a delay from initial symptom to
diagnosis of greater than 3 months, most still presented
with leukocoria and few of the extraocular signs.
Table 2. Clinical staging at diagnosis according to the
Reese-Ellsworth Classification.
Table 3. Clinical staging at diagnosis based on the International
Classification for Intraocular Retinoblastoma.
Financial cost was the most common reason for delay
from onset to diagnosis. However, this study failed to
determine the nature of the financial burden that could
include cost of consultation, laboratory tests, or travel to
a medical facility. Future data gathering should include
reasons for the delay from onset to diagnosis so that appropriate
public-health measures could be undertaken.
Majority of cases presented in the advanced intraocular
stage for both unilateral and bilateral RB cases. Decreasing
the occurrence of extraocular RB through early
consultation would further increase survival of patients.
The onset of disease has not changed over the years. Although
consultation remained delayed (mean delay of 9.1
months for unilateral and 5.9 months for bilateral cases),
results showed that the lag time had become shorter and
patients were brought in earlier for consultation (Figure
2). This may be a result of greater public awareness, improved public-health programs, and increased access to
health facilities.
Because of proximity, most of the patients were from
Luzon, specifically Metro Manila and the surrounding
provinces of Cavite, Laguna, Bulacan, and Rizal. There
were some referrals from the 3 major island groups of the
country, but many were treated at local centers with inadequate
facilities and expertise. We recommend, therefore,
a national retinoblastoma registry to assess the nationwide
incidence. In addition, we recommend the establishment
of RB treatment centers in key provinces in the Philippines.
Since the major cause of delay from onset to diagnosis was
financial such as transportation costs, there is a need to
establish regional centers with qualified eye MDs that will
be accessible, adequate, and affordable.
In summary, accessibility to medical care leading to
early consultation and treatment will definitely increase
survival rates in this potentially fatal disease.
Figure 1. Presenting signs/symptoms of retinoblastoma.
Figure 2. Decreasing trend in the delay from onset to diagnosis of
retinoblastoma.