Neonatal Retinoblastoma

(Neonatal) Retinoblastoma in the First Month of LifeDavid H. Abramson, MD; Ted T. Du, MD; Katherine L. Beaverson, MS

Objectives: To identify patients with retinoblastomawhose conditions were diagnosed at the age of 1 monthor younger and to describe their clinical features (in-cluding ocular and patient survival) and the develop-ment of second nonocular tumors.

Materials and Methods: A retrospective study of 1831patients. The cumulative incidence of second cancer de-velopment was analyzed using the Kaplan-Meier method.

Results: Forty-six patients were identified as having adiagnosis of retinoblastoma at the age of 1 month oryounger (mean age, 18.5 days). Family history (31 pa-tients [67%]) exceeded leukocoria (6 patients [13%]) asthe most common reason for detection. Twenty-six (56%)of the 46 patients were seen with unilateral retinoblas-toma, with 22 ultimately developing cancer in the fel-low eye. At the initial diagnosis, 81 (85%) of the 95 tu-mors were detected in zones 1 and 2. Eighty-two (93%)of the 88 subsequent tumors were located in zones 2 and3. In the 26 patients who had unilateral retinoblastoma,16 of the initially affected eyes and 21 of the fellow eyeswere salvaged. In the 19 (44%) of 20 patients who wereseen initially with bilateral retinoblastomas, 31 (82%) of

the 38 eyes were salvaged. The mean follow-up was 10.9years. The incidence of second nonocular cancers reached54% by 23.7 years for the patients who received radia-tion therapy, while the incidence was 0% for the pa-tients who did not. Four(8.7%) of the 46 patients devel-oped metastatic disease and died; 3 of these patients haddocumented metastases in the first month of life (one atbirth).

Conclusions: The most common manifesting sign of chil-dren diagnosed as having retinoblastoma in the first monthof life is family history. Eyes with Reese-Ellsworth groupI retinoblastomas were the most common. In patients withbilateral and unilateral retinoblastoma, new (subse-quent) ocular tumors developed in a centrifugal pat-tern. Despite an early diagnosis, patients eyes came toenucleation, and metastatic disease and death occurredfrom ocular metastases. In patients who received radia-tion therapy, the probability of developing second no-nocular cancer is 54% by 23.7 years; no second cancersdeveloped in patients who did not receive radiationtherapy.

Arch Ophthalmol. 2002;120:738-742

C HILDREN WHO have retino-blastoma usually receiveits diagnosis at a youngage. In the United Statesthe mean age at diagnosisfor unilaterally affected children is 25months; while for bilaterally affected pa-tients, it is 15 months.1 When there is aknown family history and children arescreened for the disease, the mean age atdiagnosis is younger than 1 year.2

Prior studies have demonstrated someinteresting differences exhibited by chil-dren whose condition was diagnosed in thefirst year of life2 and those whose condi-tion was diagnosed in the first 6 monthsof life.3 Some of these are expected, oth-ers are unexpected. As expected, not onlyare these childrens condition diagnosedat a younger age, but also their laterality

is different (more commonly bilateralwhen diagnosed in the first year and 6months), and their proclivity to developsubsequent intraocular tumors after treat-ment is greater. Surprisingly, despite thediagnosis within 1 year, or even 6 monthsof life, the most common intraocularReese-Ellsworth group at diagnosis wasgroup V (ie, massive tumors involvingmore than half of the retina and vitreousseeding) and the most common manifest-ing sign or symptom was leukocoria.1,2

As education to families with the heri-table form of the retinoblastoma gene hasexpanded and molecular and cytogenetictechniques become more available, wehave been examining children whose con-ditions are diagnosed at even earlier agesand we realized that the subset of chil-dren whose conditions are diagnosed in

CLINICAL SCIENCES

From the Robert M. EllsworthOphthalmic Oncology Center,New York PresbyterianHospitalWeill Cornell MedicalCollege, New York, NY.

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the first month of life had some very unusual and in-structive features. Because there are no studies on thissubset of children, we reviewed our experience at the Rob-ert M. Ellsworth Ophthalmic Oncology Center, New YorkPresbyterian Hospital, New York.

RESULTS

DEMOGRAPHICS

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

LATERALITY

Of the 46 children whose conditions were diagnosed inthe first month of life, 26 were seen with unilateral tu-mors; 20 were seen with bilateral tumors. However, 22(85%) of the 26 patients who were seen with a unilat-eral tumor developed tumors in the fellow eye. Thus, 42patients (91%) eventually had bilateral disease during ourfollow-up period.

INITIAL TREATMENT

Prior to 1990, 21 (84%) of the 25 patients received ex-ternal beam radiotherapy as their initial treatment. Af-

ter 1990, however, none of the 21 patients were treatedinitially or subsequently by irradiation.

DEVELOPMENT OF SECONDNONOCULAR TUMORS

None of the patients who were treated without irradia-tion have developed second cancers to date, with a me-dian follow-up of 4 years. Six of the patients who re-ceived irradiation developed second nonocular tumors(Figure). All second tumors were in the headthere were2 pinealomas, 2 soft tissue sarcomas, 1 osteosarcoma, and1 fibrous histiocytoma. Life-table analysis revealed that

Table 1. Patient Demographics

VariableNo. (%)

of Patients

SexMale 18 (39)Female 28 (61)

Family history of retinoblastomaPositive 33 (72)Negative 10 (22)Unknown 3 (6)

Patients age at diagnosis, dMedian (range) 18.5 (1-30)With unilateral disease 19.5With bilateral disease 17.0

Initial manifesting signFamily history 31 (67)Leukocoria 6 (13)Other 9 (20)

Strabismus 1Proptosis 1Failure to thrive 1Draining fresh blood at birth 1During routine eye examination 1A funny look 2Unknown 2

No. of tumors at manifestion, No. per eye*Mean (range) 1.9 (1-8)With unilateral disease 1.6With bilateral disease 2.0

*Only 34 of the 46 patients were included because the number of tumorsfor 12 patients was not documented.

Table 2. Tumor Location*

Variable

Location

Zone 1 Zone 2 Zone 3

No. (%) of Patients With Unilateral DiseasePresenting eye 18 (67) 6 (22) 3 (11)Subsequent tumor in

the fellow eye2 (9) 11 (48) 10 (43)

New tumor in either eye 4 (14) 8 (30) 15 (56)

No. (%) of Patients With Bilateral DiseasePresenting eyes 26 (38) 31 (46) 11 (16)New tumor in either eye 0 15 (39) 23 (61)

*Only 34 of the 46 patients were included because the location of thetumor for 12 patients was not documented.

Eleven (65%) of 17 patients developed new tumors.

MATERIALS AND METHODS

A retrospective medical record review was carried outof all patients examined by us at the Robert M. Ells-worth Ophthalmic Oncology Center and who werediagnosed as having retinoblastoma in the first 4 weeksof life. Forty-six patients were identified; 25 pa-tients received their diagnosis before 1990 and 21since 1990. The following clinical data were col-lected: sex, family history, age at diagnosis (in days),manifesting signs and symptoms, laterality, eyes in-volved at the initial visit, stage of ocular disease, meannumber of tumors, location of tumors, developmentof new ocular tumors (number and location of tu-mors, if any), development of second nonocular tu-mor, initial treatment of the tumor, length of follow-up, survival of the individual eye, and survival of thepatient. Tumor location was characterized by cen-tral vs peripheral retina, using a standard retinal draw-ing with a macular center with a classification sys-tem that was previously published.4 Zone 1, theposterior pole, encompassed a circle centered at themacula with a radius of 1 disc diameter beyond theoptic nerve. Zone 2, the equatorial zone, spanned fromthe periphery of zone 1 to the equator. Zone 3 in-cluded the anterior retina from the periphery of zone2 to the ora serrata.4 Incidence of second cancer wasanalyzed by life-table analysis as described previ-ously.5 Trilateral (pinealomas) retinoblastomas wereclassified as second nonocular neoplasms.



the incidence of second cancers in the patients who wereirradiated was 56.4% by 23.7 years.

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 seenat birth with bilateral retinoblastoma and concurrent meta-static disease. Eight (17%) of the 46 patients died dur-ing our follow-up, 4 died of metastatic retinoblastoma,and 4 died of second nonocular cancer.

COMMENTS

Our medical record review included 46 patients who hadhad the diagnosis of retinoblastoma made in the first 4weeks of life. To our knowledge, this is the largest collec-tion of neonatal retinoblastoma reported and reports bothnew information and clarifies prior, smaller reports.

Neonatal cancer is estimated to occur between 1 in16666 births6 and 1 in 12500 births.7 This translates into130 cases a year in the United States; half are diagnosedin the first 24 hours of life. Although not all series agree,the most common neonatal cancers are leukemia, sar-comas, teratomas, neuroblastomas, and central nervoussystem tumors. In some series no cases of retinoblas-toma were found. For example, in a review from Mel-bourne, Australia, from 1939 to 1989, there were no reti-

noblastomas in the series of 46 neonatal cancers.8

Similarly, in the report from the Childrens Hospital ofPhiladelphia of 22 neonates with cancer, none had reti-noblasoma.9 Some other series do report an occasionalcase of neonatal retinoblastoma. Of 99 cases of neonatalcancer collected from the West Midlands Health Author-ity Region (United Kingdom) between 1960 and 1989,2 cases of retinoblastoma were found.10 Of 23 neonateswith cancer from Duke University, Durham, NC, 4 hadretinoblastoma.11 In Toronto, Ontario, where there is alarge retinoblastoma center, 17 cases of neonatal retino-blastoma were reported in a total of 102 children withneonatal cancer.12 Thus, the series of 42 patients that wereport represents more than 50% of all cases ever re-ported and the largest collected from 1 institution. A num-ber of features of these patients suggest that they are aspecial group of children with some distinct and differ-ent characteristics.

In a previous retrospective medical record review of1265patientsof all ageswith retinoblastoma fromourcen-ter, 32 distinct manifesting signs were identified.13 The 4most 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 historyis themorecommonmanifesting sign.Forexample,of158children who were diagnosed as having retinoblastomain the first 6 months of life, it has previously been reportedthat 16% were seen because of family history.3 For patientsin this study manifesting signs were the reverse of the gen-eral retinoblastoma population: 67% (31 patients) wereseen because of a family history and 13% (6 patients) wereseen because of leukocoria. Despite the very early age atdiagnosis, 13% were still seen because of leukocoria.

The correlation between tumor detection time andretinal topography followed a central-to-peripheral dis-tribution. At the initial examination, most tumors werelocated posterior to the equator (regardless of lateral-ity), while subsequent new tumors were usually locatedanterior to the original tumors and never in the fovea.In fact, most patients and eyes developed subsequent, ad-ditional tumor foci after diagnosis and successful treat-ment of the manifesting tumors. This central-to-peripheral (centrifugal) development of new tumorshas been previously documented in eyes with bilateralretinoblastomas and has important practical implica-tions for the clinicians and the patients.4 For clinicians,

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Incidence of second nonocular cancers following the diagnosis ofretinoblastoma in patients who received radiotherapy.

Table 3. Ocular Survival of the Diseased Eyes

Variable

Reese-Ellsworth Classification GroupDiseased

Eyes RetainedI II III IV V Unknown

No. (%) of patients with initial unilateral diseasePresenting eye (n = 26) 11 (42.0) 3 (11.5) 2 (7.7) 1 (3.8) 6 (23.0) 3 (11.5) 16 (62.0)Fellow eye with subsequent tumor (n = 22) 8 (36.0) 2 (9.0) 3 (13.6) 2 (9.0) 1 (4.5) 6 (27.0) 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)

No. of diseased eyes retained byReese-Ellsworth classification group

39 (98) 9 (82) 8 (100) 4 (80) 1 (9) 7 (64) 68 (79)

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



it means that they should expect to see subsequent new,anteriorly situated tumors in the eyes of patients with bi-lateral retinoblastomas independent of the method of treat-ing the eye. For the patient (and clinician), the observa-tion that a new, subsequent tumor never developed inthe fovea is reassuring. It is also useful to inform fami-lies that these new tumors are usual and expected. Thefollow-up schedule for patients whose conditions werediagnosed in the first month of life must be adjusted sothat these tumors are detected at an early stage.

In this study, 22 (85%) of the 26 patients who ini-tially were seen with tumors in 1 eye eventually devel-oped bilateral disease. Previous study showed that 20%of the patients having unilateral disease diagnosed in thefirst 6 months of life subsequently developed bilateral dis-ease.3 Clinicians must be aware (and they must informfamilies) that children diagnosed as having unilateral reti-noblastoma in the first month of life will usually go onto develop bilateral disease.

As summarized in Table 3, the most common intra-ocular 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 4disc diameters, all at or behind the equator). This was alsotrue of the cohort of patients whose conditions were di-agnosed in the first 3 months of life14 but not true of thosewhose conditions were diagnosed in the first 6 months3

or 12 months of life.2 Though this was expected, it is worthemphasizing that despite the early age at diagnosis 13%of these eyes were classified as group V eyes at the initialvisit; early age of diagnosis does not guarantee an early stageof intraocular (or extraocular) disease.

We successfully salvaged 68 (79%) of the 86 dis-eased eyes: 16 (62%) of the 26 manifesting eyes, 21 (95%)of the 22 fellow eyes that subsequently developed tu-mors, and 31 (82%) of the 38 eyes in patients who wereseen with bilateral disease. Although all bilateral eyes withReese-Ellsworth group I through III classifications (ie,group II: solitary tumor, 4-10 disc diameters, at or be-hind the equator and multiple tumors, 4-10 disc diam-eters, behind the equator; group III: any lesion anteriorto the equator and solitary tumor, 10 disc diameters,behind the equator) were initially managed withoutenucleation, progressive disease forced us into enucle-ation in 1 (2%) of the 40 eyes in group I, 2 (8%) of the11 eyes in group II, and 1 (20%) of the 5 eyes in groupIV (ie, multiple tumors, some 10 disc diameters andany lesion extending anteriorly to the ora serrata). Morethan 90% (10/11) of the group V eyes required enucle-ation initially or after external beam radiotherapy. Evenwith bilateral retinoblastoma diagnosed in the first 4 weeksof life, we still had to enucleate 18 (21%) of the 86 dis-eased eyes, especially when the eyes were classified asReese-Ellsworth group V.

Retinoblastoma occurs in 2 formsgerminal andnongerminal. All patients who have bilateral disease ora positive family history are assumed to have the germi-nal mutation.15,16 In this study, 42 of 46 patients even-tually developed bilateral disease. Of the remaining 4 pa-tients who have unilateral disease, 3 had a positive familyhistory and 1 had an unknown family history. There-fore, at least 45 (98%) of these 46 patients had the ger-

minal mutation. Clinicians must keep this fact in mindwhen decisions are made about the treatment (espe-cially external beam irradiation) and follow-up of uni-lateral retinoblastoma when the condition is diagnosedduring the first month of life.

Second nonocular cancers in children with the ger-minal form of retinoblastoma are well known.17-23 The cu-mulative incidence of second cancer is 1% per year, reach-ing 51% (SD, 6.2%), 50 years after the diagnosis ofretinoblastoma.24 Factors that have been shown to con-tribute to this include the presence of the RB1 mutation,treatment with radiation, dose of radiation, presence of li-pomas, and recently, patient age at irradiation.23,25,26

Prior reports of neonatal retinoblastoma suggest ahigh incidence of second cancers. For example, in thereport on neonatal cancer from Denmark, 2 cases of reti-noblastoma were found and 1 patient died of a subse-quent second cancer (osteosarcoma).27 Similarly, of the4 neonatal retinoblastomas reported from Duke Univer-sity, 2 patients developed trilateral retinoblastoma.11 Ofthe 14 cases reported with neonatal retinoblastoma fromthe United Kingdom, 3 patients developed trilateral reti-noblastoma and 2 others developed sarcomas in the ir-radiated field.

Although our data suggest similar alarming pat-terns, we must be careful in drawing firm conclusionsbecause of the few patients in our study. However, wehave almost equal numbers of patients with bilateral reti-noblastoma whose conditions were diagnosed in the firstmonth of life treated with radiotherapy (21 patients) orwithout irradiation (25 patients). Follow-up is differentfor these 2 groups, as all of the patients who received ra-diation therapy were treated before 1990 (and, there-fore, have a longer follow-up period) and most of thosewho did not receive radiotherapy have been treatedsince 1990 (with a shorter follow-up period). Life tablesare usually used to adjust for such problems but in ourseries most of the patients who received no irradiationhave been diagnosed and followed up for fewer than 10years.

Life-table analysis of the irradiated group (21 pa-tients) revealed a second cancer incidence of more than56.4% by 23.6 years after the diagnosis of retinoblas-toma. Not only is this higher than the 1% per year inci-dence but it is also higher than the 2% per year that wepreviously reported in children irradiated in the first yearof life. This strongly suggests that the children with bi-lateral retinoblastoma diagnosed and treated in the firstmonth of life are at the highest risk for the developmentof second cancers.

Although follow-up is relatively short for the pa-tients who did not receive irradiation based on the re-sults here and in prior publications that have demon-strated a low but important increased incidence of secondcancers in patients with nonirradiated retinoblastoma, wesuspect that the differences between the patients who wereirradiated and not irradiated will prove to be statisti-cally and clinically significant.

If radiotherapy for ocular tumors is contemplatedin the patients whose condition was diagnosed in the firstmonth of life, the consequences for subsequent secondcancer development must be carefully weighed and ex-



plained to the family. Not only are these children at riskfor subsequent second cancers, they may actually be evenmore susceptible to the harmful effects of irradiation be-cause of their early age.

In general, children with neonatal cancers havepoor survival rates compared with older children whowere diagnosed as having cancer. Although many dosurvive, the death rate (approximately 50%) and com-plications of treatment are significant. Prior reportshave also emphasized a high death rate in children withneonatal retinoblastoma. For example, of the 17 casesreported from Toronto, 4 patients (24%) died. Of the 4cases reported from Duke University, 2 patients died ofretinoblastoma. Four (8.7%) of our patients died ofmetastatic retinoblastoma. In 1 case metastatic diseasewas evident at birth. In 2 others metastatic disease wasdetected within the first month of life. A fourth casehad buphthalmos and rupture of the globe during sur-gery, leading to orbital tumor and metastatic disease.Children detected with retinoblastoma in the firstmonth of life may manifest and/or develop metastaticdisease and die. The very early diagnosis of retinoblas-toma is still associated with significant mortality.

Twenty-eight (61%) of our 46 patients were girls.While this did not attain statistical significance in ourstudy, 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 diag-nosed in the first month of life did well, although someof these children did not develop central vision (be-cause of tumors in the macula of one or both eyes),some did not retain their eyes, some died of metastaticdisease, and many progressed to develop fatal secondcancers apparently related to the therapeutic radiationthat effectively cured the ocular cancer. The very earlydiagnosis of retinoblastoma does not guarantee vision,ocular, or patient survival and may have contributed tosubsequent death from second nonocular cancers.

Submitted for publication June 7, 2001; final revision re-ceived February 12, 2002; accepted February 28, 2002.

This study was supported in part by a grant from theSam and May Rudin Family Foundation, New York, NY (DrAbramson).

Corresponding author and reprints : David H. Abram-son, MD, 70 E 66th St, New York, NY 10023 (e-mail:[email protected]).

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18. Jensen RD, Miller RW. Retinoblaostoma: epidemiologic characteristics. N EnglJ Med. 1971;285:307-311.

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