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(Neonatal) Retinoblastoma in the First Month of Life
David H. Abramson, MD;
Ted T. Du, MD;
Katherine L. Beaverson, MS
Arch Ophthalmol. 2002;120:738-742.
ABSTRACT
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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.
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 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 children 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.
INTRODUCTION
CHILDREN WHO have retinoblastoma 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 children's condition
diagnosed at a younger age, but also their laterality 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 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.
MATERIALS AND METHODS
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 follow-up, 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.
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.
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Table 1. Patient Demographics
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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. After 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 1). All second tumors were in the head—there were 2
pinealomas, 2 soft tissue sarcomas, 1 osteosarcoma, and 1 fibrous histiocytoma.
Life-table analysis revealed that the incidence of second cancers in the patients
who were irradiated was 56.4% by 23.7 years.
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Incidence of second nonocular cancers following the diagnosis of
retinoblastoma in patients who received radiotherapy.
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OCULAR SURVIVAL AND PATIENT SURVIVAL
Patients' ocular survival, categorized by the Reese-Ellsworth 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.
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Table 3. Ocular Survival of the Diseased Eyes
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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 16 666 births6 and 1 in 12 500 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 retinoblastomas in the series of 46 neonatal cancers.8
Similarly, in the report from the Children's 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-to-peripheral ("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, 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 Reese-Ellsworth
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 forms—germinal 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 germinal 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 explained 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.
AUTHOR INFORMATION
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{at}aol.com).
From the Robert M. Ellsworth Ophthalmic Oncology Center, New York Presbyterian
Hospital–Weill Cornell Medical College, New York, NY.
REFERENCES
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1. Abramson DH, Ellsworth RM, Grumbach N, Kitchin FD. Retinoblastoma: survival, age at detection and comparison 1914-1958,
1958-1983. J Pediatr Ophthalmol Strabismus. 1985;22:246-250.
PUBMED
2. Abramson DH, Servodidio CA. Retinoblastoma in the first year of life. Ophthalmic Paediatr Genet. 1992;13:191-203.
ISI
| PUBMED
3. Abramson DH, Notterman RB, Ellsworth RM, Kitchin FD. Retinoblastoma treated in infants in the first six months of life. Arch Ophthalmol. 1983;101:1362-1366.
ABSTRACT
4. Abramson DH, Gombos DS. The topography of bilateral retinoblastoma lesions. Retina. 1996;16:232-239.
FULL TEXT
|
ISI
| PUBMED
5. Wong FL, Boice JD Jr, Abramson DH, et al. Cancer incidence after retinoblastoma-radiation dose and sarcoma risk. JAMA. 1997;278:1262-1267.
ABSTRACT
6. Bader JL, Miller RW. US cancer incidence and mortality in first year of life. AJDC. 1979;133:157-159.
7. Barson AJ. Congenital neoplasia: the society's experience: paediatric Pathology
Society. Arch Dis Child. 1978;53:46.
8. Werb P, Scurry J, Ostor A, Fortune D, Attwood H. Survey of congenital tumors in perinatal necropsies. Pathology. 1992;24:247-253.
ISI
| PUBMED
9. Gale GB, D'Angio GJ, Uri A, Chatten J, Koop CE. Cancer in neonates: the experience at the Children's Hospital of Philadelphia. Pediatrics. 1982;70:409-413.
FREE FULL TEXT
10. Parkes SE, Muir KR, Southern L, Cameron AH, Darbyshire PJ, Stevens MC. Neonatal tumors: a thirty-year population-based study. Med Pediatr Oncol. 1994;22:309-317.
ISI
| PUBMED
11. Halperin EC. Neonatal neoplasms. Int J Radiat Oncol Biol Phys. 2000;47:171-178.
FULL TEXT
|
ISI
| PUBMED
12. Campbell AN, Chan HSL, O'Brien A, Smith CR, Becker LE. Malignant tumours in the neonate. Arch Dis Child. 1987;62:19-23.
ABSTRACT
13. Abramson DH, Frank CM, Susman M, Whalen MP, Dunkel IJ, Boyd NW. Presenting signs of retinoblastoma. J Pediatr. 1998;132:505-508.
FULL TEXT
|
ISI
| PUBMED
14. Rubenfeld M, Abramson DH, Ellsworth RM, Kitchin FD. Unilateral vs bilateral retinoblastoma: correlations between age at
diagnosis and stage of ocular disease. Ophthalmology. 1986;93:1016-1019.
ISI
| PUBMED
15. Abramson DH, Ellsworth RM, Grumbach N, Sturgis-Buckhout L, Haik BG. Retinoblastoma: correlation between age at diagnosis and survival. J Pediatr Ophthalmol Strabismus. 1986;23:174-177.
PUBMED
16. Shields JA, Augsburger JJ. Current approaches to the diagnosis and management of retinoblastoma. Surv Ophthalmol. 1981;25:347-372.
FULL TEXT
|
ISI
| PUBMED
17. Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst. 1993;85:1121-1128.
FREE FULL TEXT
18. Jensen RD, Miller RW. Retinoblaostoma: epidemiologic characteristics. N Engl J Med. 1971;285:307-311.
19. Moll AC, Imhof SM, Bouter LM, Tan KE. Second primary tumors in patients with retinoblastoma: a review of
the literature. Ophthalmic Genet. 1997;18:27-34.
ISI
| PUBMED
20. Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology. 1988;95:1583-1587.
ISI
| PUBMED
21. Abramson DH, Ellsworth RM, Kitchin DF, Tung G. Second nonocular tumors in retinoblastoma survivors: are they radiation-induced? Ophthalmology. 1984;91:1351-1355.
ISI
| PUBMED
22. Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer. 1986;53:661-671.
ISI
| PUBMED
23. Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: a
possible age effect on radiation-related risk. Ophthalmology. 1998;105:573-579.
FULL TEXT
|
ISI
| PUBMED
24. Abramson DH, Dunkel IJ, McCormick B. Neoplasms of the eye. Cancer Medicine. Hamilton, Ontario: BC Decker Inc; 2000:1083-1096.
25. Abramson DH. Second nonocular cancers in retinoblastoma: a unified hypothesis: the
Franceschetti Lecture. Ophthalmic Genet. 1999;20:193-204.
FULL TEXT
| PUBMED
26. Moll AC, Imhof SM, Schouten-Van-Meeteren AY, Kuik DJ, Hofman P, Boers M. Second primary tumors in hereditary retinoblastoma: a register-based
study, 1945-1997: is there an age effect on radiation-related risk? Ophthalmology. 2001;108:1109-1114.
FULL TEXT
|
ISI
| PUBMED
27. Borch K, Jacobsen T, Olsen JH, Hirsch F, Hertz H. Neonatal cancer in Denmark. Pediatr Hematol Oncol. 1992;9:209-216.
ISI
| PUBMED
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