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© 1999 American Society for Clinical Oncology Trilateral Retinoblastoma: A Meta-Analysis of Hereditary Retinoblastoma Associated With Primary Ectopic Intracranial RetinoblastomaFrom the Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland. Address reprint requests to Tero Kivelä, MD, Department of Ophthalmology, Helsinki University Central Hospital, Haartmaninkatu 4 C, PL 220, FIN-00029 HYKS, Helsinki, Finland; email tero.kivela{at}helsinki.fi
PURPOSE: To obtain refined knowledge regarding trilateral retinoblastoma (TRb), which is a syndrome that consists of hereditary retinoblastoma associated with an intracranial neuroblastic tumor. MATERIALS AND METHODS: Using a systematic literature review, we contacted authors to obtain missing information. Data from 106 children were used in a meta-analysis including frequency distributions and Kaplan-Meier survival curves. RESULTS: TRb showed no sex predilection. Median age at diagnosis of retinoblastoma was 5 months (range, 0 to 29 months); age at diagnosis was younger among 47 children (47%) with familial retinoblastoma compared with age at diagnosis among 52 children (53%) with sporadic retinoblastoma (2 v 6.5 months, P < .0001). TRb usually affected the second or third generation with retinoblastoma. Median time from retinoblastoma to TRb was 21 months (range, 6 months before to 141 months after); time to TRb was longer for 78 (77%) pineal tumors compared with 23 (23%) suprasellar tumors (32 v 6.5 months, P < .0001). The size (27 v 32 mm, P = .57) and prognosis (survival of 9 v 8 months, P = .91) of pineal and suprasellar tumors were similar. TRb was detected earlier (1 v 22 months, P = .0007) and the child survived longer if neuroimaging was routinely performed (16 v 8 months, P = .001), but age at death was similar (36 v 37 months, P = .98). Cumulative 5-year survival (which was likely to indicate cure) was 27% (v 0%) if screening was undertaken. All children whose TRb exceeded 15 mm in size died. CONCLUSION: The family history, age at diagnosis, and laterality of retinoblastoma in children with TRb resembled that of ordinary hereditary retinoblastoma. Suprasellar TRb were diagnosed earlier, and may arise earlier, than pineal TRb. Screening by neuroimaging could improve the cure rate if cases of TRb were detected when tumors were 15 mm or smaller in size.
RETINOBLASTOMA (Rb) is the most common intraocular malignancy of children. It is caused by inactivation of both copies of a tumor suppressor gene (Rb1), which participates in the control of cell cycling.1-3 All bilateral tumors and one tenth of unilateral tumors are caused by a germline mutation inherited as an autosomal dominant trait.4,5 Children with hereditary Rb are also prone to have second cancers later in life, and some develop benign retinomas or retinocytomas.6 Trilateral retinoblastoma (TRb) is a well-recognized syndrome that consists of unilateral or bilateral hereditary Rb associated with an intracranial neuroblastic tumor.7,8 The latter arises most often in the pineal region but can also be a suprasellar or parasellar tumor, and it is considered to be an independent primary focus. TRb was first reported in 19719,10 and was differentiated from cerebral metastasis in 1977.11 TRb is important from both a theoretical and a clinical point of view. Children with familial Rb are suggested to have a particularly high incidence of TRb.8,12-16 Children who develop TRb are thought to have an earlier than usual onset of Rb7,12,13,15,17-19 and an excess of bilateral Rb,7,8,18 suggesting that TRb is caused by a different allele than that which causes ordinary Rb.7,16 The apparent incidence of TRb is increasing because of greater awareness.13,15,20,21 It is a major cause of death among children with Rb.15,20-22 Whether or not screening might improve this situation is disputed.8,12,15,16,18,19,23-26 In order to be able to manage children with Rb in an increasingly effective manner, a systematic meta-analysis of all published cases of TRb was conducted.7-25,27-65
Definitions In this article, Rb refers to intraocular tumor and TRb refers to intracranial tumor, either a pineal neuroblastic tumor (PNT) or an ectopic intracranial neuroblastic tumor (EINT) elsewhere in the brain. These names are not intended to imply the cell or cells of origin of TRb, which are still elusive.7,23,26
Systematic Literature Search The following data were extracted from each article that described a child with TRb: sex (completeness of data, 92%), age at diagnosis of Rb (90%), laterality of Rb (95%), family history for Rb (92%), affected relatives (60%), age at diagnosis of TRb (94%), site of TRb (95%), largest diameter of TRb (47%), whether TRb was diagnosed at screening (77%), whether treatment was intended to be curative (73%), survival after TRb (82%), and survival status at last follow-up (87%). When the largest diameter of TRb was not stated, it was estimated from the published computed tomography and nuclear magnetic resonance images to the nearest 5 mm. If the aforementioned data were not available from the original article, the authors were contacted to obtain the missing data. Likewise, if the child had been alive at last follow-up, updated survival information was requested; nine of 17 (53%) authors responded. The systematic literature search identified 104 children with TRb. Special care was taken to identify those who had been reported multiple times (44 children had been described two to six times) so that data could be combined. Two children treated at the Helsinki University Central Hospital were added to the final data set, which comprised 106 children.
Statistical Methods of Meta-Analysis
None of the continuous variables were normally distributed, and median and range are given as descriptive statistics. Cumulative frequency distributions for age at diagnosis of Rb, age at diagnosis of TRb, and time from Rb to TRb were plotted, from which it can be determined by which time any specified proportion of Rb and TRb were diagnosed. Frequencies in 2 x 2 and larger contingency tables were compared with Fisher's exact and Pearson's Survival times were analyzed with the Kaplan-Meier product-limit method.67 Survival between unordered and ordered categories was compared with the log-rank test and log-rank test for trend, respectively. Single death from intercurrent disease was treated as a censored observation. Equality of follow-up was ascertained by comparing survival curves with reverse censoring.67 Unless otherwise stated, statistics are based on the comparison of cases with complete data. Cases with missing categorical data were analyzed as a separate category to confirm that these cases did not systematically differ from cases included in the main analysis. In case the data did not seem to be missing at random, the cumulative frequency distribution for the cases with missing categorical data was also plotted.
Sex Of 97 children who developed TRb, 47 were boys (48%; 95% confidence interval [CI], 38 to 59) and 50 were girls (52%; 95% CI, 41 to 62). The male-to-female ratio of children who later developed a PNT was similar to that of those who developed an EINT (Table 1).
Age at Diagnosis of Intraocular Rb
Laterality of Rb
Family History for Rb Of 33 known affected relatives of 28 children, two siblings had only TRb (6%; 95% CI, 1 to 20), seven relatives had unilateral Rb (21%; 95% CI, 9 to 39), and 24 had bilateral Rb (73%; 95%, 54 to 87). One generation was affected in two families (two siblings), two generations were affected in 24 families (five siblings, 23 parents, and two uncles), and three generations were affected in three families (three parents, two grandparents, and a third cousin). In three families, at least one member who was inferred to carry mutated Rb1 had no Rb or TRb.
TRb
Age at Diagnosis of TRb
Children with EINT were younger than those with PNT (Table 2; Fig 2D). Of 82 tumors, 21 (26%) were found at screening and 61 (74%) when symptoms of increased intracranial pressure developed. The former children were younger than the latter children (median, 12 v 26 months; P = .0045; Mann-Whitney U test) (Fig 2E). If unspecified screening was considered an indication of no screening, a presumption supported by the frequency distributions (Fig 2E), then this difference persisted (P = .0014).
Time From Rb to TRb Median time from Rb to TRb was longer for familial compared with sporadic Rb (24 v 18 months, P = .012 Mann-Whitney). Time from Rb to EINT was shorter than time from Rb to PNT (Table 2; Fig 2G). The interval was also shorter for children whose TRb was found at screening as compared with those who developed symptoms (1 v 22 months; P = .0007) (Fig 2H). Of TRb cases found at screening, 50% were present when Rb was diagnosed, and 75% of such TRb cases were EINT (Fig 2H).
Largest Size of TRb TRb diagnosed by screening tended to be smaller than TRb found after symptoms developed (median, 20 v 30 mm; P = .081; Mann-Whitney U test). Of 15 TRb detected at screening, five (33%; 95% CI, 12 to 62) were 15 mm or less in size, as compared with three of 31 TRb (10%; 95% CI, 2 to 26) detected after symptoms developed (P = .092; Fisher's exact test).
Treatment of TRb
Survival After TRb Median survival time after TRb was 9 months (range, 0 to 168 months) (Fig 3A). Survival times of children who had unilateral and bilateral Rb (median, 7 v 9 months; P = .55; log-rank test), sporadic and familial Rb (8 v 8 months; P = .87), and PNT and EINT (Table 2; Fig 3B) did not differ from each other.
Probability of survival was greater for children who had a small TRb (
Age at Death
This systematic literature search identified 104 children with trilateral retinoblastoma, as compared with conventional reviews that recently reported on 64 to 80 children.26,63,65 The meta-analysis, which was based on data updated from original authors, consequently provides the most complete and accurate data currently available on TRb. It provides clinically informative cumulative frequency distributions and survival data that can be used by ophthalmologists, pediatricians, oncologists, and geneticists who manage patients with retinoblastoma, and the data set can be used to test concepts on the pathogenesis of TRb. The estimated proportion of TRb associated with familial Rb was 43% to 47%, which is substantially lower than the 55% to 71% figure that is often cited.13,14,26,62 The present estimate may even be high, because many cases of TRb were reported from large centers that treat an excess of familial Rb.14 Indeed, two centers cited a proportion almost as high for familial Rb in general, ie, 38% of all children with hereditary Rb who are seen.14,19 Even though Rb in children with TRb was diagnosed at the median age of 5 months, which is lower than average for hereditary Rb in general,8 the age at diagnosis is biased by the high proportion of familial Rb among reported children with TRb, who were likely screened for Rb after birth.36,41,43 Indeed, the median age at diagnosis of Rb in children with a positive family history was 2 months, and the cumulative frequency distribution for children with sporadic Rb resembled that reported for sporadic bilateral Rb in general in many centers, with a median age of 6 to 7 months.15,43 If TRb were caused by a stronger than average allele of mutated Rb1, one would expect to see more affected children with sporadic Rb than with familial Rb,14 and more siblings with Rb rather than affected relatives in prior generations, because TRb is almost invariably fatal. In most families, however, TRb actually developed in the second or third generation. Furthermore, the frequencies of no intraocular Rb, unilateral Rb, and bilateral Rb resembled those typical of hereditary Rb in general,5 both among children with TRb and among their affected relatives. Considering all evidence together, the meta-analysis suggests that most children with TRb have ordinary hereditary Rb that is complicated by TRb by chance.8,41 Data from large centers estimate the chances of TRb developing to be less than 0.5% among all unilateral Rb, 5% to 13% among sporadic bilateral Rb, and 5% to 15% among familial bilateral Rb.14-16,19,21,22,62 The similarity of the latter two estimates supports the idea that TRb would not be specifically associated with familial Rb. Given this estimated chance of TRb developing, one would expect approximately every tenth sibling with Rb to have TRb. Families with two siblings with TRb have indeed been reported,17,21 but information on family members in general was not detailed enough to allow estimation of the frequency of TRb among siblings by meta-analysis. It has been emphasized that a latent period of one to several years is typical between the appearance of Rb and TRb, and that by the time TRb develops, the treatment of Rb is usually completed.13,18,19,33,59,63 This delay was germane when the concept of TRb was evolving, because it provided an argument against intracranial metastasis.8,11,20,21,33 In reality, many children presented with symptoms attributable to TRb.17,19,29,30,38,63 Moreover, the meta-analysis suggested that routine screening might detect 75% of TRb cases within a year of Rb diagnosis, most of them concurrently with Rb.18 Children with TRb who developed a PNT were older than those who had an EINT in the chiasmal region.8,16-19,63,64 It has often been suggested that the latter would cause symptoms earlier because of higher potential for neurologic deficit, CSF obstruction, and tumor dissemination.18-20,63 The meta-analysis found no difference in size of PNT and EINT, however, indicating that EINT either is initiated earlier or it progresses faster than PNT. Similar slopes of cumulative frequency curves for time from Rb to TRb and similar survival after TRb would favor earlier initiation. The different age at diagnosis may thus have a biologic rather than an anatomic basis,8 justifying a clinical distinction between PNT and EINT. The fact that EINT followed a time course roughly similar to that of intraocular Rb suggests that Rb and EINT might have a more closely related histogenesis than Rb and PNT. Indeed, in two transgenic mouse models of TRb, only EINT develops.68-70 In a third strain, however, Rb is associated with PNT.71,72 The meta-analysis revealed no other primary differences between PNT and EINT. The shorter interval from Rb to EINT and the earlier age at death after EINT reflect the earlier age at diagnosis of EINT as compared with that of PNT. Unilateral Rb tended to be more common in children with EINT.63 This may reflect the fact that cases of EINT were diagnosed earlier, and Rb in the fellow eye might not yet have developed by that time.73 The meta-analysis confirmed that median survival after TRb was significantly longer if screening was performed.16,26 The age at which TRb was detected by screening was proportionally earlier, however, and the age at death did not differ between the two groups, indicating that the longer survival was largely due to lead time bias.16 On balance, the actuarial survival of screened children stabilized at 27% (95% CI, 3 to 52) after 5 years, by which time all those who had not been screened were dead of TRb. The three cured children received systemic chemotherapy with or without neuraxis irradiation and intrathecal chemotherapy.16,24 Meta-analysis suggested that screening was effective if TRb was found when it was 15 mm or less by largest diameter. The tumors of the five children without evidence of TRb were 7, 14, and 15 mm in size.16,18,24 Two children with 15-mm tumors who died received only palliative therapy,53,60 a third one died of metastatic disease after orbital recurrence,19 and a fourth one died of recurrent TRb after radiotherapy.20 The prognosis of patients with TRb between 15 and 30 mm in size did not differ from that of patients with larger tumors, suggesting that 15 mm is a critical size for dissemination through CSF. Suggested screening programs for detecting TRb have varied widely.15,16,18,19,22,25,26,51,62 The meta-analysis showed that one half of TRb cases that were detected by screening were found at baseline and one quarter were found during the following year; thereafter, the detection rate remained constant until all tumors had been detected by 4 years. It would therefore seem rational to screen every 3 months during the first year after diagnosis of Rb,24,41 and at least two times a year for the next 3 years. It is advisable to use magnetic resonance imaging to reduce radiation exposure and risk of second cancers.15,16,25 This method also detects drop metastases efficiently.47 Based on the cumulative frequency curve and the 8% to 10% average risk of TRb developing, one can calculate that approximately one in 100 scans of children with bilateral or familial Rb would be positive.14-16,21,22,62 Roughly one half of tumors would be smaller than 15 mm when detected. The cost-effectiveness of screening will heavily depend on the mortality profile. In industrialized countries, TRb is a major cause of death from hereditary Rb and already outnumbers death from metastatic Rb and second cancers in some centers.15,20-22 In spite of the relatively low frequency of a positive scan and consequently high cost of screening, this might perhaps justify a randomized multicenter study to confirm the benefit of routine neuroimaging.
I thank the following physicians for sharing updated clinical summaries of their patients: Dr Niels Ehlers, Denmark; Dr Yoichi Katayama, Japan; Dr Anette C. Moll, The Netherlands; Dr Judith E. Kingston, United Kingdom; and Dr Ghassan K. Bejjani, Dr Edward G. Buckley, Dr Eugene M. Helveston, Dr Gordon K. Klintworth, and Dr Jerry A. Shields, United States.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests, respectively, and distributions of continuous variables were compared with the Mann-Whitney U test.
15 v 16 to 30 v > 30 mm; P = .023; log-rank test for trend) 
