Trilateral RetinoblastomaIs the Location of the Intracranial Tumor Important?

Arnold C. Paulino, M.D.

Department of Radiotherapy, Cardinal BernardinCancer Center and Ronald McDonald Children’sHospital, Loyola University Medical Center, May-wood, Illinois.

Address for reprints: Arnold C. Paulino, M.D., Di-vision of Radiation Oncology, The University ofIowa Hospitals and Clinics, 200 Hawkins Drive,Room W189-Z, Iowa City, IA 52242.

Received June 15, 1998; revision received October19, 1998; accepted December 10, 1998.

BACKGROUND. Trilateral retinoblastoma refers to bilateral retinoblastoma associ-

ated with an intracranial primitive neuroectodermal tumor in the pineal or supra-

sellar region. The purpose of this study was to review patient and tumor charac-

teristics and treatment outcome in patients with trilateral retinoblastoma and to

determine whether there is a difference in presentation or outcome according to

the location of the intracranial tumor.

METHODS. A MEDLINE search of all English language articles pertaining to trilat-

eral retinoblastoma published between 1977–1997 was performed. A total of 94

different cases were identified and analyzed.

RESULTS. The gender was male in 39 patients (41.5%), female in 50 patients

(53.2%), and unknown in 5 patients (5.3%). Family history for retinoblastoma

was positive in 44 patients (46.8%), negative in 39 patients (41.5%), and un-

known in 11 patients (11.7%). The median age at the time of diagnosis of

retinoblastoma was 6 months. The median time interval to the development of

an intracranial tumor from the time of diagnosis of retinoblastoma was 21

months. In 78 patients (83.0%) the intracranial tumor was in the pineal region

and in 16 patients (17.0%) it was in the suprasellar region. The median time

interval from the time of diagnosis of retinoblastoma to the development of a

pineal region tumor was 24 months whereas the median time interval for the

development of a suprasellar region tumor was 1 month. At 6 months after the

diagnosis of intraocular tumors, 6 of 61 children with pineal region tumors and

10 of 14 patients with suprasellar region tumors had developed intracranial

disease (P 5 0.005). Unilateral intraocular retinoblastoma associated with in-

tracranial tumor was more likely to occur in patients with suprasellar region

tumors than pineal region tumors (P , 0.015). The median survival after the

diagnosis of an intracranial tumor was 6 months regardless of the location of

the intracranial tumor. For patients who received no treatment for the intra-

cranial tumor the median survival was 1 month whereas it was 8 months for

those who received treatment. Children who were asymptomatic at the time of

diagnosis of the intracranial tumor had a better overall survival than those who

were symptomatic (P 5 0.002).

CONCLUSIONS. The prognosis of children who develop trilateral retinoblastoma is

dismal with current treatment strategies. Tumors of the suprasellar region present

earlier than tumors of the pineal region after the diagnosis of intraocular tumors.

Because patients who were asymptomatic at the time of diagnosis of intracranial

disease had a better overall survival than those who were symptomatic, screening

for intracranial tumors may be a valuable strategy in the management of patients

with bilateral and/or hereditary retinoblastoma. [See editorial on pages 3–5, this

issue.] Cancer 1999;86:135– 41. © 1999 American Cancer Society.

KEYWORDS: trilateral retinoblastoma, intracranial tumor, childhood cancer, radio-therapy, chemotherapy, screening.

135

© 1999 American Cancer Society

The trilateral retinoblastoma syndrome is a rarecondition that traditionally refers to bilateral reti-

noblastoma in association with an ectopic intracranialtumor indistinguishable histologically from the in-traocular tumors. The association first was describedin detail by Jakobiec et al. in 19771 and the term“trilateral retinoblastoma” was popularized in 1980 byBader et al.2 When Bader et al. described their initialten cases with trilateral retinoblastoma, the intracra-nial tumors identified were located in the pineal glandregion.2 Since that time, multiple reports have identi-fied a location in the suprasellar region associatedwith bilateral retinoblastoma. The purpose of thisstudy was to determine whether there is a differencein presentation or outcome in relation to the locationof the intracranial tumor in children with trilateralretinoblastoma. An additional aim of the study was toprovide patient and tumor characteristics, pattern offailure analysis, and treatment outcome in patientswith this unusual entity.

METHODSA MEDLINE search of all English language articlesbetween 1970 –1997 pertaining to trilateral retinoblas-toma was performed and identified a total of 125cases.1,3-42 Table 1 lists the authors, institutions, andthe number of cases described in each study. Overlapof case reports occurred in some patients2– 4,12–13,

16 –17,19 –23,25–26,28,30 –31,33,35–37,39 – 40,42 and after correc-tion for repetition of cases a total of 94 different chil-dren with trilateral retinoblastoma was identified.Special attention was paid to characteristics of thehost and tumor, treatment, patterns of failure, andoutcome; family history of retinoblastoma also wasexamined. An attempt was made to contact the firstauthors of the articles when important informationregarding the patient and tumor characteristics waslacking.

The Fisher exact test was employed to determinewhether there was a difference in the time intervalfrom the time of the diagnosis of retinoblastoma to theoccurrence of an intracranial tumor between childrenwho developed tumors of the pineal and suprasellarregions. Likewise the same test was used to determinewhether unilateral intraocular retinoblastomas withgermline mutations were more likely to be associatedwith the suprasellar region than pineal tumors. Sur-vival estimates of children who were symptomatic andasymptomatic were calculated using the Kaplan–Meier method43; the log rank test was employed tocompare survival curves of patients who were symp-tomatic and asymptomatic at the time of diagnosis forintracranial disease.

RESULTSPatient and Tumor CharacteristicsGender was male in 39 patients (41.5%), female in 50patients (53.2%), and unknown in 5 patients (5.3%). Afamily history of retinoblastoma was found to be pos-itive in 44 patients (46.8%), negative in 39 patients(41.5%), and unknown in 11 (11.7%). The median ageat the time of diagnosis of an intraocular tumor was 6months.

Eighty-five patients had bilateral retinoblastomaassociated with an intracranial tumor. Nine of the 85children with bilateral retinoblastoma who subse-quently developed an intracranial primitive neuroec-todermal tumor (PNET) had asynchronous intraoculartumors. Laterality of initial ocular involvement wasknown in eight of nine asynchronous patients; fourhad initial right eye involvement and four had initialleft eye involvement.

Seven children with trilateral retinoblastoma whowere reported in the literature had a unilateral retino-blastoma with germline mutation associated with anintracranial tumor. In two patients, the unilateral in-traocular tumor was diagnosed at the same time as theintracranial tumor; for the remaining five patients, thetime interval from the diagnosis of the eye tumor tothe development of the brain tumor ranged from 4 –30months (median, 12 months). Of the seven patientswith unilateral retinoblastoma and an associated in-tracranial malignancy, four had right intraocular tu-mors and three had left intraocular tumors; four chil-dren had tumors of the suprasellar region and threechildren had tumors of the pineal region. A unilateralintraocular tumor associated with an intracranialPNET was more likely to be found in the suprasellarregion than in the pineal region (4 of 16 patients vs. 3of 78 patients; P 5 0.015).

Two patients had intracranial tumors (one in thesuprasellar region and the other in the pineal region)in the absence of intraocular disease. Both patientshad a sibling with bilateral retinoblastoma; one siblinghad a tumor in the pineal region in addition to bilat-eral intraocular tumors.

Intracranial TumorIntracranial tumor location was known in all patients.Seventy-eight children (83.0%) had tumor of the pi-neal region and 16 (17.0%) had a PNET of the supra-sellar region. The median time interval from the diag-nosis of an intraocular tumor to the development ofan intracranial neoplasm for 75 evaluable childrenwas 21 months. Figure 1 shows the various time inter-vals for all evaluable patients according to the locationof the intracranial tumor.

136 CANCER July 1, 1999 / Volume 86 / Number 1

For the 16 patients with suprasellar tumors, 9patients (56.3%) were female, 6 patients (37.5%) weremale, and the gender was unknown in 1 patient(6.3%). The median time interval from the diagnosis ofan ocular tumor to the development of an intracranialtumor was 1 month. In two children, the tumor in thesuprasellar region preceded bilateral intraocular tu-mors. Six children (37.5%) with tumors of the supra-sellar region had a positive family history of retino-blastoma.

For the 78 patients with pineal region tumors,the gender was female in 41 patients (52.6%),

male in 33 patients (42.3%), and unknown in 4 pa-tients (5.1%). The median time interval from thediagnosis of an intraocular tumor to the develop-ment of a pineal region tumor was 24 months. Thir-ty-eight children (48.7%) with tumors of the pinealregion had a positive family history of retinoblas-toma.

At 6 months after the diagnosis of intraoculartumors, 6 of 61 evaluable children with tumors of thepineal region and 10 of 14 children with tumors of thesuprasellar region had developed intracranial disease(P 5 0.005).

TABLE 1Studies Reporting Cases of Trilateral Retinoblastoma

AuthorsYear ofpublication Institution No. of cases

Jakobiec et al.1 1977 George Washington University, Washington, DC 2Bullitt and Crain3 1981 Duke University, Durham, NC 1Judisch and Shivanand4 1981 University of Iowa, Iowa City, IA 1Bader et al.5 1982 National Cancer Institute, Bethesda, MD 14Zimmerman et al.6 1982 University of Missouri, Columbia, MO 1Dudgeon and Lee7 1983 University of Glasgow, Glasgow, United Kingdom 2Ehlers et al.8 1983 University of Aarhus, Aarhus, Denmark 1Brownstein et al.9 1984 McGill University, Montreal, Canada 2Michaud et al.10 1984 University of Montreal, Montreal, Canada 1Tarkkanen et al.11 1984 University of Helsinki, Helsinki, Finland 1Johnson et al.12 1985 Children’s Hospital National Medical Center, Washington, DC 3Kingston et al.13 1985 St. Bartholomew’s Hospital, London, United Kingdom 12Stannard et al.14 1985 University of Cape Town, Cape Town, South Africa 1Whittle et al.15 1985 Royal Alexandria Hospital for Children, Sydney, Australia 1Lueder et al.16 1986 University of Iowa, Iowa City, IA 3Malik et al.17 1986 Duke University, Durham, NC 2Meadows18 1986 Children’s Hospital of Philadelphia, Philadelphia, PA 1Towbin and Bisset19 1986 University of Cincinnati, Cincinnati, OH 1Helveston et al.20 1987 Indiana University, Indianapolis, IN 1Bomanji et al.21 1989 St. Bartholomew’s Hospital, London, United Kingdom 1Pesin and Shields22 1989 Wills Eye Hospital, Philadelphia, PA 7Shields et al.23 1989 Wills Eye Hospital, Philadelphia, PA 1Schwartz et al.24 1990 Medical College of Virginia, Richmond, VA 1Holladay et al.25 1991 Indiana University, Indianapolis, IN and University of Cincinnati, Cincinnati, OH 3Lueder et al.26 1991 University of Iowa, Iowa City, IA 4Mukherjee et al.27 1991 Diwan Aggarwal Research Center, New Delhi, India 1Nelson et al.28 1992 Duke University, Durham, NC 3Stolovitch et al.29 1992 Ichilov Hospital Tel Aviv, Israel 1Marks et al.30 1993 Duke University, Durham, NC 1Scott and Richard31 1993 University of Oklahoma, Oklahoma City, OK 3Blach et al.32 1994 Memorial Sloan-Kettering Cancer Center, New York, NY 6DePotter et al.33 1994 Wills Eye Hospital, Philadelphia, PA 13Finelli et al.34 1995 Case Western University, Cleveland, OH 2McCormack et al.35 1995 University of Oklahoma, Oklahoma City, OK 1Nunna et al.36 1995 All India Institute, New Delhi, India 1Provenzale et al.37 1995 Duke University, Durham, NC 1Amoaku et al.38 1996 West Midlands Regional Children’s Tumour, Research Group, Birmingham, United Kingdom 5Bagley et al.39 1996 Wills Eye Hospital, Philadelphia, PA 10Bejjani et al.40 1996 George Washington University, Washington, DC 1Moll et al.41 1996 Dutch Retinoblastoma Register, Amsterdam, The Netherlands 7Skulski et al.42 1997 University of Cincinnati, Cincinnati, OH 1

Trilateral Retinoblastoma/Paulino 137

Treatment Outcome and Pattern of FailureThe median survival after a diagnosis of intracranialtumor for all patients was 6 months. The mediansurvivals for children with tumors of the pineal region(range, 0 –96 months) and PNETs of the suprasellarregion (range, 0 –23 months) both were 6 months. Themedian survival for children who received no treat-ment for the intracranial tumor was 1 month whereasit was 8 months for children who were treated for theintracranial tumor. Table 2 lists the 6 patients whosurvived at least 2 years after the diagnosis of anintracranial tumor. All six children had a pineal regiontumor. Treatment included chemotherapy in all sixchildren and craniospinal irradiation (CSRT) wasgiven to four patients. The type of treatment given forthe intracranial tumor in all patients is shown in Table3. The most common type of treatment was chemo-therapy in combination with radiation therapy (RT)followed by RT alone. Eighteen patients receivedCSRT; 15 of these patients developed disseminatedneuraxis disease despite CSRT. Forty-one of the 75evaluable patients (54.7%) died with disseminatedneuraxis disease.

Survival rates for children who were symptomaticand those who were asymptomatic at the time ofdiagnosis of intracranial disease were compared andshowed a statistically significant survival advantagefor patients with asymptomatic intracranial disease(Fig. 2) (P 5 0.002).

DISCUSSIONIn this review of trilateral retinoblastoma from 1977–1997, four groups of children were identified with re-gard to the presentation of intraocular tumors in re-lation to the intracranial tumor. The most commonpresentation found in 76 of 94 children (80.1%) wasthe “traditional” definition of trilateral retinoblasto-ma: synchronous bilateral intraocular tumors ob-served in association with a PNET of the pineal orsuprasellar region. Bilateral retinoblastoma may beasynchronous and may be associated with an intra-cranial tumor. Such was the case in 9 of 94 children(9.6%). The third group of children included 7 patients(7.4%) with a unilateral retinoblastoma with a germ-line mutation and intracranial PNET; this first wasdescribed by Whittle et al.,15 who coined the term“forme fruste” of trilateral retinoblastoma for this pre-sentation. Our study showed that tumors of the supra-sellar region were more likely to be associated withunilateral intraocular tumors when compared withtumors of the pineal region. Finally, two children withgermline mutations did not have an intraocular tumorbut had an intracranial PNET; one patient had a sib-

ling with bilateral retinoblastoma and the other hadan identical twin with trilateral retinoblastoma.

The pineal region presentation is more frequentthan the suprasellar region presentation. There ap-peared to be no difference based on gender or familyhistory between patients with tumors in the suprasel-lar region and those with tumors in the pineal region.Regardless of intracranial location, trilateral retino-blastoma was detected more frequently in girls thanboys. The median time interval from the diagnosis ofan intraocular tumor to the development of an intra-cranial tumor was 21 months. Suprasellar region tu-mors presented earlier than pineal region PNETs. Itappears that 89% and 98.7% of all patients with trilat-eral retinoblastoma developed intracranial disease at4 years and 7 years, respectively, from the time of theinitial diagnosis of an intraocular tumor. This infor-mation is important for physicians who treat childrenwith bilateral retinoblastoma because screening forintracranial tumors would be most helpful during thefirst 4 years after the diagnosis of an intraocular tu-mor. A small but significant proportion of childrenwith bilateral or hereditary retinoblastoma developintracranial disease. At the Memorial Sloan-KetteringCancer Center, 6% of patients with bilateral retino-blastoma and 10% of patients with a family history ofretinoblastoma developed intracranial PNET.32 An-other report from the Wills Eye Hospital showed thattrilateral retinoblastoma occurred in 13 of 440 consec-utive children with retinoblastoma (3%).33 Some mayargue that screening for trilateral retinoblastoma maynot be very helpful given the median survival of only 6months and the small number of patients with bilat-eral or hereditary retinoblastoma who develop intra-cranial disease. However, in 1 study trilateral retino-blastoma accounted for 6 of 12 deaths (50%) duringthe first 5 years after the diagnosis of retinoblastoma.32

Trilateral retinoblastoma is an underappreciatedcause of mortality in the first 5 years after the diagno-sis of bilateral retinoblastoma.

Screening for intracranial disease in children withbilateral and hereditary retinoblastoma may be bene-ficial because our study showed that patients whowere asymptomatic at the time of diagnosis of intra-cranial disease had a better survival compared withthose who were symptomatic. Screening may be per-formed by the use of magnetic resonance imaging ofthe brain. It is not clear how often brain imagingshould be performed except that it should be per-formed for at least 4 years after the diagnosis of in-traocular tumors. In a report from Duke University,the 2 longest survivors (at 33 months and 96 months,respectively, after the diagnosis of an intracranial tu-mor) were diagnosed using routine imaging of the

138 CANCER July 1, 1999 / Volume 86 / Number 1

brain prior to the development of symptoms.28 Datafrom the Wills Eye Hospital also argue for the screen-ing of children with bilateral retinoblastoma. In a se-ries of 13 patients, children who were asymptomatichad a significantly longer survival compared withthose who were symptomatic (P 5 0.05).33 DePotter etal. recommend screening for intracranial tumors inchildren with bilateral and/or familial retinoblastomauntil age 4 years.33 This recommendation can be mod-ified further using the results of our analysis, whichshowed that 89% of patients will have developed anintracranial tumor 4 years after the initial diagnosis ofintraocular retinoblastoma.

Treatment for trilateral retinoblastoma resulted ina median survival of 8 months. There was no differ-ence in survival outcome regardless of whether thetumor was in the pineal versus the suprasellar region.Of the 6 children who survived . 2 years after adiagnosis of intracranial PNET, all received chemo-therapy and 4 received CSRT. For the 75 evaluablechildren in whom the pattern of failure was reported,41 (54.7%) had disseminated neuraxis disease. Only 3

of 18 children who received CSRT achieved control oftumor dissemination along the neuraxis; 2 of thesechildren received chemotherapy. Therefore, efforts inachieving a cure for this tumor should be directedtoward the prevention of tumor dissemination alongthe neuraxis. The use of chemotherapy and CSRT ap-pears to be reasonable because this form of treatmentwas used in four of six “long-term” survivors. Further-more, the use of chemotherapy and CSRT resulted in3-year overall and progression free survival rates of57% and 45%, respectively, in children with primarysupratentorial PNET treated on a Children’s CancerGroup protocol.44 In a retrospective study of 36 chil-dren at the Hospital for Sick Children in Toronto, allsix survivors with primary PNET of the brain receivedCSRT and four received chemotherapy.45

Certainly, there are limitations in this report. First,this is a 20-year review of patients treated using avariety of therapeutic approaches. The data gathered

FIGURE 1. Time intervals between the diagnosis of an intraocular tumor and

the development of an intracranial neoplasm according to the location of the

intracranial tumor in 75 evaluable children with trilateral retinoblastoma.

FIGURE 2. Comparison of overall survival rates after a diagnosis of intra-

cranial tumor according to symptomatology. Children who were asymptomatic

for intracranial disease at the time of diagnosis had a better overall survival

than children who were symptomatic at the time of diagnosis (P 5 0.002).

TABLE 2Treatment Characteristics of Patients Surviving at Least 2 Years afterthe Diagnosis of an Intracranial Tumor

Case no.Survival(mos) Treatment

4 31 CSRT 1 CCNU, VCR40 96 CPM, MTX, ARA-C, HYDRO41 33 CSRT 1 CPM, ARA-C, HYDRO45 26 CSRT 1 CPM, MTX, VCR, DOX69 30 Unspecified chemotherapy78 28 CSRT 1 unspecified chemotherapy

CSRT: craniospinal irradiation; CCNU: lomustine; VCR: vincristine; CPM: cyclophosphamide; MTX:

methotrexate; ARA-C: cytosine arabinoside; HYDRO: hydrocortisone; DOX: doxorubicin.

TABLE 3Type of Treatment of Intracranial Tumors in the 94 Children withTrilateral Retinoblastomas

CSRT 1 chemotherapy 25CSRT alone 20No treatment 16Unknown 12Chemotherapy alone 10CSRT 1 surgery 6Chemotherapy 1 surgery 2CSRT 1 chemotherapy 1 surgery 2Surgery alone 1

RT: radiation therapy.

Trilateral Retinoblastoma/Paulino 139

from each case were not all complete because somearticles did not evaluate all the patient, tumor, andtreatment characteristics. Another potential problemwith this study is that we do not know whether theearly detection of intracranial disease in asymptom-atic patients produces a lag time bias similar to thatobserved in the detection of women with breast car-cinoma using mammography.

The median survival of children with trilateral ret-inoblastoma is dismal regardless of the location of theintracranial tumor. Pineal region tumors occur morefrequently than suprasellar PNET. Children with tu-mors of the suprasellar region develop intracranialdisease earlier and are more likely to have intracranialdisease associated with unilateral intraocular retino-blastoma with germline mutations when comparedwith children with tumors of the pineal region. Inchildren with bilateral or hereditary retinoblastoma,screening for intracranial disease for at least 4 yearsmay be warranted because patients who are asymp-tomatic at the time of diagnosis of an intracranialtumor have been found to have a better overall sur-vival than patients who were symptomatic. Efforts tocontrol this disease should be directed toward theprevention of tumor dissemination along the neuraxis,which is a pattern of failure observed in . 50% ofpatients.

REFERENCES1. Jackobiec FA, Tso MOM, Zimmerman LE, Davis P. Retino-

blastoma and intracranial malignancy. Cancer 1977;39:2048 –58.

2. Bader JL, Miller RW, Meadows AT, Zimmerman LE, Cham-pion LAA, Voute PA. Trilateral retinoblastoma. Lancet 1980;2:582–3.

3. Bullitt E, Crain BJ. Retinoblastomas as a possible primaryintracranial tumor. Neurosurgery 1981;9:706 –9.

4. Judisch GF, Shivanand RP. Concurrent hereditable retino-blastoma, pinealoma and trisomy X. Arch Ophthalmol 1981;99:1767–9.

5. Bader JL, Meadows AT, Zimmerman LE, Rorke LB, Voute PA,Champion LAA, et al. Bilateral retinoblastoma with ectopicintracranial retinoblastoma: trilateral retinoblastoma. Can-cer Genet Cytogenet 1982;5:203–13.

6. Zimmerman LE, Burns RP, Wankum G, Tully R, Esterly JA.Trilateral retinoblastoma: ectopic intracranial retinoblas-toma associated with bilateral retinoblastoma. J PediatrOphthalmol Strabismus 1982;19:320 –5.

7. Dudgeon J, Lee WR. The trilateral retinoblastoma syndrome.Trans Ophthalmol Soc UK 1983;103:523–9.

8. Ehlers N, Kaal S, Rasmussen K, Ratjen E. Hereditary bilateralretinoblastoma, pinealoma and normal chromosomes: acase report. Acta Opthalmol (Copenh) 1983;61:838 – 43.

9. Brownstein S, de Chadarevian JP, Little JM. Trilateral reti-noblastoma: report of two cases. Arch Ophthalmol 1984;102:257– 62.

10. Michaud J, Jacob JL, Demers J, Dumas J. Trilateral retino-

blastoma: bilateral retinoblastoma with pinealoblastoma.Can J Ophthalmol 1984;19:36 –9.

11. Tarkkanen A, Haltia M, Karjalainin K. Trilateral retinoblas-toma. Pineoblastoma (ectopic intracranial retinoblastoma)associated with bilateral retinoblastoma. Ophthalmic Pae-diatr Genet 1984;4:1– 6.

12. Johnson DL, Chandra R, Fisher WS, Hammock MK, McKe-own CA. Trilateral retinoblastoma: ocular and pineal retino-blastomas. J Neurosurg 1985;63:367–70.

13. Kingston JE, Plowman PN, Hungerford JL. Ectopic intracra-nial retinoblastoma in childhood. Br J Ophthalmal 1985;69:742– 8.

14. Stannard C, Knight BK, Sealy R. Pineal malignant neoplasmin association with hereditary retinoblastoma. Br J Ophthal-mol 1985;69:749 –53.

15. Whittle IR, McClellan K, Martin FJ, Johnson IHl. Concurrentpineoblastoma and unilateral retinoblastoma: a formefruste of trilateral retinoblastoma? Neurosurgery 1985;17:500 –5.

16. Lueder GT, Judisch GF, O’Gorman TW. Second nonoculartumors in survivors of heritable retinoblastoma. Arch Oph-thalmol 1986;104:372–3.

17. Malik RK, Friedman HS, Djang WT, Falletta JM, Buckley E,Kurtzberg J, et al. Treatment of trilateral retinoblastomawith vincristine and cyclophosphamide. Am J Ophthalmol1986;102:650 – 6.

18. Meadows A. Trilateral retinoblastoma. Med Pediatr Oncol1986;14:323– 6.

19. Towbin RB, Bisset GS. Pediatric case of the day. Radiograph-ics 1986;6:1100 – 4.

20. Helveston EM, Knuth KR, Ellis FD. Retinoblastoma. J PediatrOphthalmol Strabismus 1987;24:296 –300.

21. Bomanji J, Kingston JE, Hungerford JL, Britton KE. 123 I-Metaiodobenzylguanidine scintigraphy of ectopic intracra-nial retinoblastoma. Med Pediatr Oncol 1989;17:66 – 8.

22. Pesin SR, Shields JA. Seven cases of trilateral retinoblastoma.Am J Ophthalmol 1989;107:121– 6.

23. Shields JA, Pesin SR, Shields CL. Trilateral retinoblastoma.J Clin Neuro Ophthalmol 1989;9:222–3.

24. Schwartz AM, Ghatak NR, Laine FJ. Intrasellar primitiveneuroectodermal tumor (PNET) in familial retinoblastoma:a variant of “trilateral retinoblastoma”. Clin Neuropathol1990;9:55–9.

25. Holladay DA, Holladay A, Montebello JF, Redmond KP. Clin-ical presentation, treatment, and outcome of trilateral reti-noblastoma. Cancer 1991;67:710 –5.

26. Lueder GT, Judisch GF, Wen BC. Heritable retinoblastomaand pinealoma. Arch Ophthalmol 1991;109:1707–9.

27. Mukherjee M, Gothi R, Doda SS, Aggarwal SK. Trilateralretinoblastoma. AJR Am J Roentgenol 1991;157:198 –9.

28. Nelson SC, Friedman HS, Oakes WJ, Halperin EC, Tien R,Fuller GN, et al. Successful therapy for trilateral retinoblas-toma. Am J Ophthalmol 1992;114:23–9.

29. Stolovitch C, Loewenstein A, Varssano D, Lazar M. Trilateralretinoblastoma. Metab Pediatr Syst Ophthalmol 1992;15:57–9.

30. Marks LB, Bentel G, Sherouse GW, Spencer DP, Light K.Craniospinal irradiation for trilateral retinoblastoma follow-ing ocular irradiation. Med Dosim 1993;18:125– 8.

31. Scott MH, Richard JM. Retinoblastoma in the state of Okla-homa: a clinicopathologic review. J Okla State Med Assoc1993;86:111– 8.

140 CANCER July 1, 1999 / Volume 86 / Number 1

32. Blach LE, McCormick B, Abramson DH, Ellsworth RM. Tri-lateral retinoblastoma - incidence and outcome: a decade ofexperience. Int J Radiat Oncol Biol Phys 1994;29:729 –33.

33. DePotter P, Sheilds CL, Shields JA. Clinical variations oftrilateral retinoblastoma: a report of 13 cases. J Pediatr Oph-thalmol Strabismus 1994;31:26 –31.

34. Finelli DA, Shurin SB, Bardenstein DS. Trilateral retinoblas-toma: two variations. AJNR Am J Neuroradiol 1995;16:166–70.

35. McCormack S, Raftery R, Palmgren D, Leonard JC. Pine-oblastoma imaged during bone scintigraphy. Clin Nucl Med1995;20:1023– 4.

36. Nunna SVV, Sharma R, Vashisht S, Berry M. Trilateral retino-blastoma: CT evaluation. Indian J Ophthalmol 1995;43:27–9.

37. Provenzale JM, Weber AL, Klintworth GK, McLendon RE.Radiographic-pathologic correlation. Bilateral retinoblas-toma with coexistent pineoblastoma (trilateral retinoblasto-ma). AJNR Am J Neuroradiol 1995;16:157– 65.

38. Amoaku WMK, Willshaw HE, Parkes SE. Trilateral retino-blastoma. A report of five patients. Cancer 1996;78:858 – 63.

39. Bagley LJ, Hurst RW, Zimmerman RA, Shields JA, Shields CL,DePotter P. Imaging in trilateral retinoblastoma syndrome.Neuroradiology 1996;38:166 –70.

40. Bejjani GK, Donahue DJ, Selby D, Cogen PH, Packer R.Association of a suprasellar mass and intraocular retinoblas-toma: a variant of pineal trilateral retinoblastoma? Ped Neu-rosurg 1996;25:269 –75.

41. Moll AC, Imhaf SM, Bouter LM, Kuik DJ, Den Otter W,Bezember PD, et al. Second primary tumors in patients withhereditary retinoblastoma: a register based follow-up study,1945-1994. Int J Cancer 1996;67:515–9.

42. Skulski M, Egelhoff JC, Kollias SS, Mazeniski C, Ball WS.Trilateral retinoblastoma with suprasellar involvement.Neuroradiology 1997;39:41–3.

43. Kaplan EL, Meier P. Nonparametric estimation from theincomplete observations. J Am Stat Assoc 1958;54:457– 81.

44. Cohen BH, Zeltzer PM, Boyett JM, Geyer JR, Allen JC, FinlayJL, et al. Prognostic factors and treatment results for supra-tentorial primitive neuroectodermal tumors in children, us-ing radiation and chemotherapy: a Children’s Cancer Grouprandomized trial. J Clin Oncol 1995;13:1687–96.

45. Dirks PB, Harris L, Hoffman HJ, Humphreys RP, Drake JM,Rutka JT. Supratentorial primitive neuroectodermal tumorsin children. J Neurooncol 1996;29:75– 84.

Trilateral Retinoblastoma/Paulino 141