CLINICAL SCIENCES

(Neonatal) Retinoblastoma in the First Month of Life

David H. Abramson, MD; Ted T. Du, MD; Katherine L. Beaverson, MS

Objectives: To identify patients with retinoblastoma

whose conditions were diagnosed at the age of 1 month
or younger and to describe their clinical features (including ocular and patient survival) and the development of second nonocular tumors.
Materials and Methods: A retrospective study of 1831
patients. The cumulative incidence of second cancer development was analyzed using the Kaplan-Meier method.

the 38 eyes were salvaged. The mean follow-up was 10.9

years. The incidence of second nonocular cancers reached
54% by 23.7 years for the patients who received radiation therapy, while the incidence was 0% for the patients who did not. Four(8.7%) of the 46 patients developed metastatic disease and died; 3 of these patients had
documented metastases in the first month of life (one at
birth).
Conclusions: The most common manifesting sign of chil-

Results: Forty-six patients were identified as having a

diagnosis of retinoblastoma at the age of 1 month or

younger (mean age, 18.5 days). Family history (31 patients [67%]) exceeded leukocoria (6 patients [13%]) as
the most common reason for detection. Twenty-six (56%)
of the 46 patients were seen with unilateral retinoblastoma, with 22 ultimately developing cancer in the fellow eye. At the initial diagnosis, 81 (85%) of the 95 tumors were detected in zones 1 and 2. Eighty-two (93%)
of the 88 subsequent tumors were located in zones 2 and
3. In the 26 patients who had unilateral retinoblastoma,
16 of the initially affected eyes and 21 of the fellow eyes
were salvaged. In the 19 (44%) of 20 patients who were
seen initially with bilateral retinoblastomas, 31 (82%) of

From the Robert M. Ellsworth

Ophthalmic Oncology Center,
New York Presbyterian
HospitalWeill Cornell Medical
College, New York, NY.

dren diagnosed as having retinoblastoma in the first month

of life is family history. Eyes with Reese-Ellsworth group
I retinoblastomas were the most common. In patients with
bilateral and unilateral retinoblastoma, new (subsequent) ocular tumors developed in a centrifugal pattern. Despite an early diagnosis, patients eyes came to
enucleation, and metastatic disease and death occurred
from ocular metastases. In patients who received radiation therapy, the probability of developing second nonocular cancer is 54% by 23.7 years; no second cancers
developed in patients who did not receive radiation
therapy.
Arch Ophthalmol. 2002;120:738-742

HILDREN WHO have retino-

blastoma usually receive

its diagnosis at a young
age. In the United States
the mean age at diagnosis
for unilaterally affected children is 25
months; while for bilaterally affected patients, it is 15 months.1 When there is a
known family history and children are
screened for the disease, the mean age at
diagnosis is younger than 1 year.2
Prior studies have demonstrated some
interesting differences exhibited by children whose condition was diagnosed in the
first year of life2 and those whose condition was diagnosed in the first 6 months
of life.3 Some of these are expected, others are unexpected. As expected, not only
are these childrens condition diagnosed
at a younger age, but also their laterality

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738

is different (more commonly bilateral

when diagnosed in the first year and 6
months), and their proclivity to develop
subsequent intraocular tumors after treatment is greater. Surprisingly, despite the
diagnosis within 1 year, or even 6 months
of life, the most common intraocular
Reese-Ellsworth group at diagnosis was
group V (ie, massive tumors involving
more than half of the retina and vitreous
seeding) and the most common manifesting sign or symptom was leukocoria.1,2
As education to families with the heritable form of the retinoblastoma gene has
expanded and molecular and cytogenetic
techniques become more available, we
have been examining children whose conditions are diagnosed at even earlier ages
and we realized that the subset of children whose conditions are diagnosed in

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Table 1. Patient Demographics

MATERIALS AND METHODS

No. (%)
of Patients

Variable

A retrospective medical record review was carried out

of all patients examined by us at the Robert M. Ellsworth Ophthalmic Oncology Center and who were
diagnosed as having retinoblastoma in the first 4 weeks
of life. Forty-six patients were identified; 25 patients received their diagnosis before 1990 and 21
since 1990. The following clinical data were collected: sex, family history, age at diagnosis (in days),
manifesting signs and symptoms, laterality, eyes involved at the initial visit, stage of ocular disease, mean
number of tumors, location of tumors, development
of new ocular tumors (number and location of tumors, if any), development of second nonocular tumor, initial treatment of the tumor, length of followup, survival of the individual eye, and survival of the
patient. Tumor location was characterized by central vs peripheral retina, using a standard retinal drawing with a macular center with a classification system that was previously published.4 Zone 1, the
posterior pole, encompassed a circle centered at the
macula with a radius of 1 disc diameter beyond the
optic nerve. Zone 2, the equatorial zone, spanned from
the periphery of zone 1 to the equator. Zone 3 included the anterior retina from the periphery of zone
2 to the ora serrata.4 Incidence of second cancer was
analyzed by life-table analysis as described previously.5 Trilateral (pinealomas) retinoblastomas were
classified as second nonocular neoplasms.

Sex
Male
Female
Family history of retinoblastoma
Positive
Negative
Unknown
Patients age at diagnosis, d
Median (range)
With unilateral disease
With bilateral disease
Initial manifesting sign
Family history
Leukocoria
Other
Strabismus
Proptosis
Failure to thrive
Draining fresh blood at birth
During routine eye examination
A funny look
Unknown
No. of tumors at manifestion, No. per eye*
Mean (range)
With unilateral disease
With bilateral disease

18 (39)
28 (61)
33 (72)
10 (22)
3 (6)
18.5 (1-30)
19.5
17.0
31 (67)
6 (13)
9 (20)
1
1
1
1
1
2
2
1.9 (1-8)
1.6
2.0

*Only 34 of the 46 patients were included because the number of tumors

for 12 patients was not documented.

Table 2. Tumor Location*

the first month of life had some very unusual and instructive features. Because there are no studies on this
subset of children, we reviewed our experience at the Robert M. Ellsworth Ophthalmic Oncology Center, New York
Presbyterian Hospital, New York.
RESULTS

DEMOGRAPHICS
Forty-six patients were identified with a mean follow-up of 10.9 years (range, 1-50.9 years; median, 4
years). Patients characteristics are listed in Table 1 and
the locations of tumors are listed in Table 2.

Location
Variable

Zone 1

Zone 2

No. (%) of Patients With Unilateral Disease

Presenting eye
18 (67)
6 (22)
Subsequent tumor in
2 (9)
11 (48)
the fellow eye
New tumor in either eye
4 (14)
8 (30)
No. (%) of Patients With Bilateral Disease
Presenting eyes
26 (38)
31 (46)
New tumor in either eye
0
15 (39)

Zone 3
3 (11)
10 (43)
15 (56)
11 (16)
23 (61)

*Only 34 of the 46 patients were included because the location of the

tumor for 12 patients was not documented.
Eleven (65%) of 17 patients developed new tumors.

LATERALITY
Of the 46 children whose conditions were diagnosed in
the first month of life, 26 were seen with unilateral tumors; 20 were seen with bilateral tumors. However, 22
(85%) of the 26 patients who were seen with a unilateral tumor developed tumors in the fellow eye. Thus, 42
patients (91%) eventually had bilateral disease during our
follow-up period.
INITIAL TREATMENT
Prior to 1990, 21 (84%) of the 25 patients received external beam radiotherapy as their initial treatment. Af(REPRINTED) ARCH OPHTHALMOL / VOL 120, JUNE 2002
739

ter 1990, however, none of the 21 patients were treated

initially or subsequently by irradiation.
DEVELOPMENT OF SECOND
NONOCULAR TUMORS
None of the patients who were treated without irradiation have developed second cancers to date, with a median follow-up of 4 years. Six of the patients who received irradiation developed second nonocular tumors
(Figure). All second tumors were in the headthere were
2 pinealomas, 2 soft tissue sarcomas, 1 osteosarcoma, and
1 fibrous histiocytoma. Life-table analysis revealed that
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noblastomas in the series of 46 neonatal cancers. 8

Similarly, in the report from the Childrens Hospital of
Philadelphia of 22 neonates with cancer, none had retinoblasoma.9 Some other series do report an occasional
case of neonatal retinoblastoma. Of 99 cases of neonatal
cancer collected from the West Midlands Health Authority Region (United Kingdom) between 1960 and 1989,
2 cases of retinoblastoma were found.10 Of 23 neonates
with cancer from Duke University, Durham, NC, 4 had
retinoblastoma.11 In Toronto, Ontario, where there is a
large retinoblastoma center, 17 cases of neonatal retinoblastoma were reported in a total of 102 children with
neonatal cancer.12 Thus, the series of 42 patients that we
report represents more than 50% of all cases ever reported and the largest collected from 1 institution. A number of features of these patients suggest that they are a
special group of children with some distinct and different characteristics.
In a previous retrospective medical record review of
1265 patients of all ages with retinoblastoma from our center, 32 distinct manifesting signs were identified.13 The 4
most common signs were leukocoria (56.2%), strabismus
(23.6%), poor vision (7.7%), and family history (6.8%).
With a younger age of diagnosis, however, family history
is the more common manifesting sign. For example, of 158
children who were diagnosed as having retinoblastoma
in the first 6 months of life, it has previously been reported
that 16% were seen because of family history.3 For patients
in this study manifesting signs were the reverse of the general retinoblastoma population: 67% (31 patients) were
seen because of a family history and 13% (6 patients) were
seen because of leukocoria. Despite the very early age at
diagnosis, 13% were still seen because of leukocoria.
The correlation between tumor detection time and
retinal topography followed a central-to-peripheral distribution. At the initial examination, most tumors were
located posterior to the equator (regardless of laterality), while subsequent new tumors were usually located
anterior to the original tumors and never in the fovea.
In fact, most patients and eyes developed subsequent, additional tumor foci after diagnosis and successful treatment of the manifesting tumors. This central-toperipheral (centrifugal) development of new tumors
has been previously documented in eyes with bilateral
retinoblastomas and has important practical implications for the clinicians and the patients.4 For clinicians,

the incidence of second cancers in the patients who were

irradiated was 56.4% by 23.7 years.
OCULAR SURVIVAL AND PATIENT SURVIVAL
Patients ocular survival, categorized by the ReeseEllsworth clinical classification system at the initial visit,
is given in Table 3. Notable is 1 patient who was seen
at birth with bilateral retinoblastoma and concurrent metastatic disease. Eight (17%) of the 46 patients died during our follow-up, 4 died of metastatic retinoblastoma,
and 4 died of second nonocular cancer.
COMMENTS

Our medical record review included 46 patients who had

had the diagnosis of retinoblastoma made in the first 4
weeks of life. To our knowledge, this is the largest collection of neonatal retinoblastoma reported and reports both
new information and clarifies prior, smaller reports.
Neonatal cancer is estimated to occur between 1 in
16666 births6 and 1 in 12500 births.7 This translates into
130 cases a year in the United States; half are diagnosed
in the first 24 hours of life. Although not all series agree,
the most common neonatal cancers are leukemia, sarcomas, teratomas, neuroblastomas, and central nervous
system tumors. In some series no cases of retinoblastoma were found. For example, in a review from Melbourne, Australia, from 1939 to 1989, there were no reti-

Incidence of Second Nonocular Cancer, %

60
50
40
30
20
10
0
0

10

20

30

40

50

60

Time After Diagnosis, y

Incidence of second nonocular cancers following the diagnosis of

retinoblastoma in patients who received radiotherapy.

Table 3. Ocular Survival of the Diseased Eyes

Reese-Ellsworth Classification Group
I

II

III

IV

Unknown

Diseased
Eyes Retained

No. (%) of patients with initial unilateral disease

Presenting eye (n = 26)
Fellow eye with subsequent tumor (n = 22)

11 (42.0)
8 (36.0)

3 (11.5)
2 (9.0)

2 (7.7)
3 (13.6)

1 (3.8)
2 (9.0)

6 (23.0)
1 (4.5)

3 (11.5)
6 (27.0)

16 (62.0)
21 (95.0)

No. (%) of patients with initial bilateral disease*

Presentation (n = 38)

21 (55.3)

6 (15.8)

3 (7.9)

2 (5.3)

4 (10.6)

2 (5.3)

31 (82)

39 (98)

9 (82)

8 (100)

4 (80)

1 (9)

7 (64)

68 (79)

Variable

No. of diseased eyes retained by

Reese-Ellsworth classification group

*One patient was excluded because the eye survival information was not documented.

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it means that they should expect to see subsequent new,

anteriorly situated tumors in the eyes of patients with bilateral retinoblastomas independent of the method of treating the eye. For the patient (and clinician), the observation that a new, subsequent tumor never developed in
the fovea is reassuring. It is also useful to inform families that these new tumors are usual and expected. The
follow-up schedule for patients whose conditions were
diagnosed in the first month of life must be adjusted so
that these tumors are detected at an early stage.
In this study, 22 (85%) of the 26 patients who initially were seen with tumors in 1 eye eventually developed bilateral disease. Previous study showed that 20%
of the patients having unilateral disease diagnosed in the
first 6 months of life subsequently developed bilateral disease.3 Clinicians must be aware (and they must inform
families) that children diagnosed as having unilateral retinoblastoma in the first month of life will usually go on
to develop bilateral disease.
As summarized in Table 3, the most common intraocular disease stage of this age group was ReeseEllsworth group I (ie, solitary tumor, 4 disc diameters,
at or behind the equator and multiple tumors, none 4
disc diameters, all at or behind the equator). This was also
true of the cohort of patients whose conditions were diagnosed in the first 3 months of life14 but not true of those
whose conditions were diagnosed in the first 6 months3
or 12 months of life.2 Though this was expected, it is worth
emphasizing that despite the early age at diagnosis 13%
of these eyes were classified as group V eyes at the initial
visit; early age of diagnosis does not guarantee an early stage
of intraocular (or extraocular) disease.
We successfully salvaged 68 (79%) of the 86 diseased eyes: 16 (62%) of the 26 manifesting eyes, 21 (95%)
of the 22 fellow eyes that subsequently developed tumors, and 31 (82%) of the 38 eyes in patients who were
seen with bilateral disease. Although all bilateral eyes with
Reese-Ellsworth group I through III classifications (ie,
group II: solitary tumor, 4-10 disc diameters, at or behind the equator and multiple tumors, 4-10 disc diameters, behind the equator; group III: any lesion anterior
to the equator and solitary tumor, 10 disc diameters,
behind the equator) were initially managed without
enucleation, progressive disease forced us into enucleation in 1 (2%) of the 40 eyes in group I, 2 (8%) of the
11 eyes in group II, and 1 (20%) of the 5 eyes in group
IV (ie, multiple tumors, some 10 disc diameters and
any lesion extending anteriorly to the ora serrata). More
than 90% (10/11) of the group V eyes required enucleation initially or after external beam radiotherapy. Even
with bilateral retinoblastoma diagnosed in the first 4 weeks
of life, we still had to enucleate 18 (21%) of the 86 diseased eyes, especially when the eyes were classified as
Reese-Ellsworth group V.
Retinoblastoma occurs in 2 formsgerminal and
nongerminal. All patients who have bilateral disease or
a positive family history are assumed to have the germinal mutation.15,16 In this study, 42 of 46 patients eventually developed bilateral disease. Of the remaining 4 patients who have unilateral disease, 3 had a positive family
history and 1 had an unknown family history. Therefore, at least 45 (98%) of these 46 patients had the ger(REPRINTED) ARCH OPHTHALMOL / VOL 120, JUNE 2002
741

minal mutation. Clinicians must keep this fact in mind

when decisions are made about the treatment (especially external beam irradiation) and follow-up of unilateral retinoblastoma when the condition is diagnosed
during the first month of life.
Second nonocular cancers in children with the germinal form of retinoblastoma are well known.17-23 The cumulative incidence of second cancer is 1% per year, reaching 51% (SD, 6.2%), 50 years after the diagnosis of
retinoblastoma.24 Factors that have been shown to contribute to this include the presence of the RB1 mutation,
treatment with radiation, dose of radiation, presence of lipomas, and recently, patient age at irradiation.23,25,26
Prior reports of neonatal retinoblastoma suggest a
high incidence of second cancers. For example, in the
report on neonatal cancer from Denmark, 2 cases of retinoblastoma were found and 1 patient died of a subsequent second cancer (osteosarcoma).27 Similarly, of the
4 neonatal retinoblastomas reported from Duke University, 2 patients developed trilateral retinoblastoma.11 Of
the 14 cases reported with neonatal retinoblastoma from
the United Kingdom, 3 patients developed trilateral retinoblastoma and 2 others developed sarcomas in the irradiated field.
Although our data suggest similar alarming patterns, we must be careful in drawing firm conclusions
because of the few patients in our study. However, we
have almost equal numbers of patients with bilateral retinoblastoma whose conditions were diagnosed in the first
month of life treated with radiotherapy (21 patients) or
without irradiation (25 patients). Follow-up is different
for these 2 groups, as all of the patients who received radiation therapy were treated before 1990 (and, therefore, have a longer follow-up period) and most of those
who did not receive radiotherapy have been treated
since 1990 (with a shorter follow-up period). Life tables
are usually used to adjust for such problems but in our
series most of the patients who received no irradiation
have been diagnosed and followed up for fewer than 10
years.
Life-table analysis of the irradiated group (21 patients) revealed a second cancer incidence of more than
56.4% by 23.6 years after the diagnosis of retinoblastoma. Not only is this higher than the 1% per year incidence but it is also higher than the 2% per year that we
previously reported in children irradiated in the first year
of life. This strongly suggests that the children with bilateral retinoblastoma diagnosed and treated in the first
month of life are at the highest risk for the development
of second cancers.
Although follow-up is relatively short for the patients who did not receive irradiation based on the results here and in prior publications that have demonstrated a low but important increased incidence of second
cancers in patients with nonirradiated retinoblastoma, we
suspect that the differences between the patients who were
irradiated and not irradiated will prove to be statistically and clinically significant.
If radiotherapy for ocular tumors is contemplated
in the patients whose condition was diagnosed in the first
month of life, the consequences for subsequent second
cancer development must be carefully weighed and exWWW.ARCHOPHTHALMOL.COM

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plained to the family. Not only are these children at risk

for subsequent second cancers, they may actually be even
more susceptible to the harmful effects of irradiation because of their early age.
In general, children with neonatal cancers have
poor survival rates compared with older children who
were diagnosed as having cancer. Although many do
survive, the death rate (approximately 50%) and complications of treatment are significant. Prior reports
have also emphasized a high death rate in children with
neonatal retinoblastoma. For example, of the 17 cases
reported from Toronto, 4 patients (24%) died. Of the 4
cases reported from Duke University, 2 patients died of
retinoblastoma. Four (8.7%) of our patients died of
metastatic retinoblastoma. In 1 case metastatic disease
was evident at birth. In 2 others metastatic disease was
detected within the first month of life. A fourth case
had buphthalmos and rupture of the globe during surgery, leading to orbital tumor and metastatic disease.
Children detected with retinoblastoma in the first
month of life may manifest and/or develop metastatic
disease and die. The very early diagnosis of retinoblastoma is still associated with significant mortality.
Twenty-eight (61%) of our 46 patients were girls.
While this did not attain statistical significance in our
study, 70% of all children with neonatal cancers are girls,11
though some series have a male preponderance.26
This cohort of patients whose condition was diagnosed in the first month of life did well, although some
of these children did not develop central vision (because of tumors in the macula of one or both eyes),
some did not retain their eyes, some died of metastatic
disease, and many progressed to develop fatal second
cancers apparently related to the therapeutic radiation
that effectively cured the ocular cancer. The very early
diagnosis of retinoblastoma does not guarantee vision,
ocular, or patient survival and may have contributed to
subsequent death from second nonocular cancers.
Submitted for publication June 7, 2001; final revision received February 12, 2002; accepted February 28, 2002.
This study was supported in part by a grant from the
Sam and May Rudin Family Foundation, New York, NY (Dr
Abramson).
Corresponding author and reprints : David H. Abramson, MD, 70 E 66th St, New York, NY 10023 (e-mail:
ICancerMD@aol.com).

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742

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