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Retinoblastoma in older Children
Retinoblastoma in Older Children CAROL L. SHIELDS, MD, JERRY A. SHIELDS, MD, PANKAJKUMAR SHAH, MD
Abstract: A review of 400 consecutive patients with retinoblastoma who pre sented to the Ocular Oncology Service at Wills Eye Hospital showed that 34 (8.5%) patients were older than 5 years of age at the time of initial diagnosis. The tumor was active in 26 (76%) cases and inactive (retinoma) in 8 (24%). An evaluation of the 26 patients with active retinoblastoma showed several unique features. At the time of diagnosis, their median age was 6 years and the oldest was 18 years. In 20 (77%) cases, the patient volunteered symptoms that prompted the eye examination; the presenting symptoms included leukocoria (9 cases), decreased vision (9 cases), strabismus (4 cases), pain (1 case), floaters (1 case), and no symptoms (2 cases). All of the 26 patients (1 00%) had unilateral sporadic retinoblastoma. Misdiagnosis before referral was common in these older children with active retinoblastoma. Five patients (19%) had prior vitrectomy for presumed vitreous hemorrhage or endophthalmitis while the ret inoblastoma was unsuspected clinically, one patient (4%) had cryotherapy for presumed Coats disease, and one (4%) was observed for 7 months for pre sumed vitreous hemorrhage. The clinician should seriously consider the pos sibility of retinoblastoma in children who present with signs of unexplained vit reous hemorrhage or endophthalmitis, even if they are older than 5 years of age. Ophthalmology 1991; 98:395-399
The incidence of retinoblastoma in the United States varies slightly, depending on the population studied, but it is generally estimated to be approximately 1:15,000 to 1:20,000 live births. 1•2 Overall, retinoblastoma occurs at an average annual incidence of 5.8 per million. 3 In the 0 to 4 years age group, the annual incidence is 10.9 per million, and in those children aged five years and older, the annual incidence of retinoblastoma is 0.6 per million. 3 There are inconsistencies in the literature regarding sur vival with retinoblastoma in these various age groups. 3- 6 Originally received: September 4, 1990. Revision accepted: December 3, 1990. From the Ocular Oncology Service, Wills Eye Hospital, Jefferson Medical College, Thomas Jefferson University, Philadelphia. Presented at the American Academy of Ophthalmology Annual Meeting, Atlanta, OctjNov 1990 Supported by the Ocular Oncology Fund and the Oncology Research Fund, Wills Eye Hospital, Philadelphia, and the Eye Tumor Research Foun dation Incorporated, Gladwyne, Pennsylvania. Reprint requests to Carol L. Shields, MD, Oncology Service, Wills Eye Hospital, Ninth and Walnut Sts, Philadelphia, PA 19107.
The average patient age at diagnosis of retinoblastoma is 24 months in unilateral cases and 13 months in bilateral cases. 7 •8 Almost 90% of all patients with retinoblastoma are diagnosed before the age of 5 years. 8 Several cases of retinoblastoma in patients of more advanced age have been reported. Retinoblastoma has been newly diagnosed in children between the ages of7 and 18 9 - 15 and has been found to occur even in adults of ages 24, 26, 45, 48, and 60 years. 16- 21 Finlay and Byron22 in 1962 reported on a 74-year-old woman with newly diagnosed retinoblastoma. The reason for the development of this tumor at such advanced age is speculative. Some authors believe that the tumor may arise from a reactivated previously un diagnosed spontaneously regressed/arrested retinoblas toma.23 Others have proposed that the persistence of an embryonal retinal cell may contribute to the unusual de velopment of the tumor at such an advanced age. 16 We report on our series of 26 cases of active retino blastoma in children who were older than 5 years of age at the time ofinitial diagnosis. We point out certain unique aspects of this group ofolder patients with retinoblastoma and alert the clinician to the potential atypical presenta tions of this malignancy in older children. 395
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Table 1. Summary of Features of Retinoblastoma in 26 Children Older than 5 Years of Age Patient No.
Age (Yrs)
1 2 3
5.1 5.1 5.1 5.2 5.3 5.3 5.4 5.5 5.6 5.7 5.7 60 6.0 6.6 6.9 7.0 7.5 8.0 8.0 8.3 10.1
4
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
12.0 13.3 16.3 17.0
18.0
Race
Sex
B
F M F M F M F M F M M F F M M M M F F F
w w B w H w w w w w w H w w w w w w B w w w B w w
M F F F M F
Initial Symptoms Strabismus Poor vision Poor vision Strabismus Leukocoria Leukocoria Strabismus Leukocoria Poor vision Leukocoria Strabismus Pain Leukocoria Poor vision None Leukocoria Poor vision Leukocoria Poor vision Leukocoria Poor vision Floaters Poor vision Leukocoria None Poor vision
Prior Treatment/ Presumed Diagnosis None None None PPV/vit hem None None None None None None PPV/vit hem PPV/Vii inflam Observe/vi! heme None None None None None None None Cryotherapy/Coats disease PPVfvit inflam None PPV/vii inflam None None
Tumor Type
Laterality Inheritance
Treatment
Status
Endophytic Endophytic Endophytic Endophytic Diffuse Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Exophytic Endophytic Endophytic Endophytic Exophytic
Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilaleral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic
Enucleation* Enucleation* Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation• Enucleation Enucleation Enucleation* Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation
Alive Alive Alive Dead Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Dead Alive Alive Alive Alive Alive Dead
Endophytic Endophytic Endophytic Endophytic Endophytic
Unilateral Unilateral Unilateral Unilateral Unilateral
EBRT Enucleation Enucleation' EBRT Enucleation
Alive Dead Alive Alive Alive
sporadic sporadic sporadic sporadic sporadic
B = black; W = white; H = hispanic; PPV = pars plana vitrectomy; vit hem =vitreous hemorrhage; vit inflam = vitreous inflammation; EBRT = external beam radiolherapy. * Supplemenlary external beam radiotherapy and/or chemotherapy given.
PATIENTS AND METHODS
RESULTS
The charts of all patients with the diagnosis of retino blastoma who presented to the Ocular Oncology Service at Wills Eye Hospital between February 1974 and June 1990 were reviewed and computer coded on detailed flowsheets, using the Macintosh program "4th Dimen sion." Those patients who were 5 years of age (60 months) or older at the time of initial diagnosis were selected for further study. Their selected computerized data were evaluated for the patient's age at initial diagnosis, race, sex, initial symptoms, and prior diagnosis and treatment. The laterality and inheritance pattern of the tumor and the method of treatment of the tumor (observation, cryo therapy, photocoagulation, plaque radiotherapy, external beam radiotherapy, enucleation, and chemotherapy) were recorded. The tumor type (endophytic, exophytic, diffuse, or spontaneous regressed/spontaneous arrested) as made both clinically during the examination on the Ocular On cology Service and histopathologically in those eyes that were enucleated was recorded. Follow-up status (alive and well, alive with metastases, dead of metastases, and dead of other causes) was noted.
There were 400 patients with the diagnosis of retino blastoma seen on the Ocular Oncology Service between February 1974 and June 1990. There were 34 (8.5%) pa tients who were 5 years or older at the time of initial diagnosis. Twenty-six of the 34 patients had active reti noblastoma, while eight patients had inactive tumors (re tinoma). The eight cases of inactive retinoma were ex cluded from this study. A complete evaluation of the 26 cases of active retinoblastoma is presented in Table l. The ages of these older patients with active tumors ranged from 5.1 years (61 months) to 18.0 years (216 months). The median age was 6.3 years (76 months) and the mean age was 8.1 years (97 months). Of the 400 patients, 6 (1.5%) were older than lO years of age, and 3 (0.8%) were older than 15 years of age at initial diagnosis. There were 20 white patients (77%), 4 black patients (17%), and 2 Hispanic patients (6% ). Fourteen of the .pa tients were female (54%) and 12 were male (46%). The tumor was unilateral in all 26 cases (100%) and remained unilateral on follow-up examinations in these cases. The retinoblastoma was sporadic (no family history of reti
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Fig I. Patient 24. Left, 16-year-old girl who presented with a hypopyon that was later determined to be an endophytic retinoblastoma after vitrectomy. Right, gross specimen of the enucleated eye in the same patient shows the fluffy, endophytic retinoblastoma.
Fig 2. Patient 13. Six-year-old girl in whom a vitreous hemorrhage de veloped that was observed for resolution and was later found to have an endophytic retinoblastoma. Notice the anterior chamber tumor nodules inferiorly.
noblastoma) in all 26 cases ( 100%). The initial symptoms included poor vision in 9 (35%) cases, leukocoria in 9 (35%) cases, strabismus in 4 (15%) cases, floaters in 1 (4%) case, pain in 1 (4%) case, and no symptoms in 2 (8%) cases. In seven (27%) cases, the tumor was either observed or given some form of treatment while the retinoblastoma was unsuspected (before referral to us). In five of these seven patients, pars plana vitrectomy had been performed for vitreous hemorrhage (2 cases) and presumed vitreous inflammation (3 cases) (Fig 1). In one case, cryotherapy for presumed Coat's disease was performed. In one case, the eye was observed for 7 months for resolution of vit reous hemorrhage of unclear etiology (Fig 2). The other 19 (73%) patients were referred to us before invasive sur gery or prolonged observation. The retinoblastoma tumors showed the following gen eral clinical patterns of growth: primarily endophytic in
22 (85%) cases, primarily exophytic in 3 (12%) cases, and diffuse in 1 (4%) case. The involved eyes were treated with enucleation in 24 (92%) cases and external beam radio therapy in 2 (8%) cases. Five patients (19%) who were managed by enucleation received supplemental external beam radiotherapy and/or chemotherapy because there was tumor invasion of the optic nerve on histopathologic examination ofthe eye (three cases) or they had undergone prior vitrectomy and there was concern that tumor cells could have been disseminated into extraocular tissues (two cases). Of the 26 patients, 4 ( 15%) have died of metastatic retinoblastoma over a mean follow-up period of 5.1 years (range, 0.5 to 13.3 years; median, 5.0 years). The meta static deaths occurred at a mean of 2.4 years (range, 1.0 to 4.7 years; median, 1.9 years) after initial diagnosis. One of these patients, a 5-year-old boy, had been initially managed by pars plana vitrectomy for unexplained vit reous hemorrhage, and another patient, a 10-year-old boy, had been treated with cryotherapy for presumed Coats' disease. The other two cases of metastatic retinoblastoma with death were in a 7-year-old boy who was found to have retrolaminar invasion of the optic nerve after enu cleation and died of metastatic disease despite aggressive chemotherapy and in a 13-year-old girl whose parents declined all treatment until the tumor eventually extended outside the eye. The parents then consented to enucle ation.
DISCUSSION In 1929, Verhoeff18 published the first American report of a histopathologically confirmed retinoblastoma in an adult, a 48-year-old man. In 1943, McCrea24 reported an authentic case of a newly diagnosed retinoblastoma in a 67-year-old patient. In this case, the patient presented with a cataract and vitreous floaters. Later Rasmussen, 19 Rychener, 25 and Mehra 17 reported on older patients with 397
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retinoblastoma who were initially diagnosed at the ages of 48, 33, and 45 years, respectively. All of these patients had atypical presentations such as pain, inflammation, conjunctival chemosis, or glaucoma. Since these initial case reports of retinoblastoma in adults, there have been several other single cases with ages at diagnosis extending up to age 74 years. 9 - 16 •20 - 23 •26 In all of these reported cases of retinoblastoma in older children, the disease was pre sumably sporadic. Retinoblastoma in older patients (older than 5 years of age) may produce atypical symptoms and signs. Most young patients (younger than 5 years of age) with reti noblastoma develop signs of leukocoria or strabismus that are initially noticed by the parents and lead to subsequent eye examination. In this series of older patients (older than 5 years of age) with retinoblastoma, we found the presenting features to be unusual in several respects. It was the child who first noticed the symptoms in 20 of the 24 cases (83%) in which symptoms were present. These included decreased vision in 9 (35%) cases, leukocoria in 9 (35%) cases, strabismus in 4 (15%) cases, floaters in 1 (4%) case, pain in 1 (4%) case, and no symptoms in 2 (8%) cases. The symptoms of decreased vision, floaters, and pain are distinctly unusual for younger children with this intraocular tumor. Atypical signs of retinoblastoma include hypopyon, hyphema, uveitis, endophthalmitis, vitreous hemorrhage, or orbital cellulitis. 9- 11 •14 •26 In our 26 cases of retinoblas toma in older children, several atypical findings of the disease were seen, often leading to misdiagnosis and de layed treatment. Six patients presented with vitreous "in flammation" and/or hemorrhage that obscured the view ofa tumor, and retinoblastoma was not initially suspected. However, many patients presented with more typical findings of leukocoria and strabismus. Stafford and associates28 suggested that these atypical manifestations carry a higher risk of death due primarily to a delay in diagnosis. They found that 15% of 618 cases of histopathologically proven retinoblastoma seen at the Armed Forces Institute of Pathology were initially mis diagnosed clinically. The misdiagnoses included pano phthalmitis, endophthalmitis, uveitis, tuberculosis, sy phylitic uveitis, sympathetic uveitis, nonspecific uveitis, glaucoma, and "pseudoglioma." In our review of lesions referred to us with the diagnosis of retinoblastoma or rule out retinoblastoma we found that toxocariasis, Coats' dis ease, and persistent hyperplastic primary vitreous were the conditions that were most commonly confused clin ically with retinoblastoma (unpublished data). Worsening survival of the patient with retinoblastoma correlates with the presence of orbital or optic nerve in volvement with the tumor.Z 9 One of the four deaths in this series was in a patient who had undergone prior pars plana vitrectomy who likely had orbital involvement. The other metastatic deaths were in a patient initially treated as Coats' disease, a patient with optic nerve invasion from retinoblastoma, and a patient whose parents refused treatment for the child. In a recent report of three patients with retinoblastoma managed with pars plana vitrectomy, 398
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metastases developed in all three patients. 3° Four of the five patients in our study who underwent vitrectomy, however, remain alive and well without metastatic disease at 14.0, 3.5, 2.5, and 1.0 years follow-up. All four patients were treated aggressively: two underwent enucleation with postoperative external beam radiotherapy and/or che motherapy, one was treated only with external beam ra diotherapy, and one had enucleation at the time of vi trectomy elsewhere after intraoperative telephone con sultation with us. Not included in this study was another older child (5 years old) that we recently evaluated with retinoblastoma who was managed by pars plana vitrec tomy for presumed intraocular inflammation that later proved to be retinoblastoma. He was treated aggressively with enucleation, external beam radiotherapy, and che motherapy, but follow-up is only 5 months. Retinoblastoma should be considered in the differential diagnosis of any child with an intraocular mass or less typical manifestations of intraocular inflammation or hemorrhage. This study has clearly shown that active ret inoblastoma can present in children older than 5 years of age and may produce atypical clinical features in such older children. The use of ancillary testing and possibly obtaining opinions by experienced observers may help make the correct diagnosis and avoid unnecessary delays in the diagnosis of these cases of retinoblastoma.
REFERENCES 1. Macklin MT. A study of retinoblastoma in Ohio. Am J Hum Genet 1960; 12:1-43. 2. Devesa SS. The incidence of retinoblastoma. Am J Opthalmol1975; 80:263-5. 3. Tambolli A, Podgor MJ, Horm JW. The incidence of retinoblastoma in the United States: 1974 through 1985. Arch Ophthalmol1990; 108: 128-32. 4. Sanders BM, Draper GJ, Kingston JE. Retinoblastoma in Great Britain 1969-80: incidence, treatment, and survival. Br J Ophthalmol 1988; 72:576-83. 5. Pendergrass TW, Davis S. Incidence of retinoblastoma in the United States. Arch Ophthalmol1980; 98:1204-10. 6. Abramson DH, Ellsworth RM, Grumbach N, et al. Retinoblastoma: correlation between age at diagnosis and survival. J Pediatr Ophthalmol Strabismus 1986; 23:174-7. 7. Shields JA. Diagnosis and Management of Intraocular Tumors St. Louis: CV Mosby, 1983; 437-533. 8. Rubenfeld M, Abramson DH, Ellsworth RM, Kitchin FD. Unilateral vs. bilateral retinoblastoma: correlations between age at diagnosis and stage of ocular disease. Ophthalmology 1986; 93:1016-9. 9. Labib MAM, EI-Gammal Y, EI-Aguizy H. Retinoblastoma; unusual pre sentation. Bull Ophthalmol Soc Egypt 1975; 68:385-9. 10. Binder PS. Unusual manifestations of retinoblastoma. Am J Ophthalmol 1974; 77:674-9. 11. Bremner MH. Retinoblastoma in the anterior chamber of the eye. Aust · J Ophthalmol 1983; 11 123-6. 12. Sheta A. Some aspects on the different clinical characteristics of ret inoblastoma. Bull Ophthalmol Soc Egypt 1971; 64:413-24. 13. Zakka KA, Yee RD, Foos RY . Retinoblastoma in a 12-year-old girl. Ann Ophthalmol1983; 15:88-91.
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14. Ohnishi Y, Yamana Y. Minei M, Yoshitomi F. Snowball opacity in ret inoblastoma. Jpn J Ophthalmol1982; 26:159-65. 15. Shields JA, Michelson JB, Leonards BC, Thompson R. Retinoblastoma in an eighteen-year-old male. J Pediatr Ophthalmol1976; 13:274-7. 16. Takahashi T, Tamura S, Inoue M, et al. Retinoblastoma in a 26-year old adult. Ophthalmology 1983; 90:179-83. 17. Mehra KS, Hamid S. Retinoblastoma in an adult. Am J Ophthalmol 1961; 52:405-6. 18. Verhoef! FH. Retinoblastoma: report of a ca9e in a man aged forty eight. Arch Ophthalmol1929; 2:643-50. 19. Rasmussen K. Retinoblastoma in a man aged forty-eight years. Acta Ophthalmol 1943; 21 :210-3. 20. Berkeley JS, Kalita BC. Retinoblastoma in an adult. Lancet 1977; 2: 508-9. 21. Sanborn GE, Augsburger JJ, Shields JA. Spontaneous regression of bilateral retinoblastoma. Br J Ophthalmol 1982; 66:685-90. 22. Finlay JR, Byron H. Retinoblastoma in the adult: review of literature and report of case associated with a benign melanoma. In: Acta XIX Concilium Ophthalmologicum (New Delhi), 1962; Vol. 2; 1168-78.
23. Lasch H. Ein Retinoblastomrezidiz im Erwachsenenalter. Klin Montsbl Augenheilk 1964; 144:268-72. 24. McCrea WBE. Glioma of the retina. A review of twelve cases. Br J Ophthalmol1943; 27:259-73. 25. Rychener RO. Retinoblastoma in the adult. Trans Am Ophthalmol Soc 1948; 46:318-26. 26. Shields JA, Shields CL, Eagle RC, Blair CJ. Spontaneous pseudo hypopyon secondary to diffuse infiltrating retinoblastoma. Arch Ophthalmol1988; 106:1301-2. 27. Makley TA Jr. Retinoblastoma in a 52-year-old man. Arch Ophthalmol 1963; 69:325-7. 28. Stafford WR, Yanoff M, Parnell BL. Retinoblastomas initially misdi agnosed as primary ocular inflammations. Arch Ophthalmol1969; 82: 771-3. 29. Kopelman JE, Mclean IW, Rosenberg SH. Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmology 1987; 94:371-7. 30. Stevenson KE, Hungerford J, Garner A. Local extraocular extension of retinoblastoma following intraocular surgery. Br J Ophthalmol1989; 73:739-42.
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Abstract: A review of 400 consecutive patients with retinoblastoma who pre sented to the Ocular Oncology Service at Wills Eye Hospital showed that 34 (8.5%) patients were older than 5 years of age at the time of initial diagnosis. The tumor was active in 26 (76%) cases and inactive (retinoma) in 8 (24%). An evaluation of the 26 patients with active retinoblastoma showed several unique features. At the time of diagnosis, their median age was 6 years and the oldest was 18 years. In 20 (77%) cases, the patient volunteered symptoms that prompted the eye examination; the presenting symptoms included leukocoria (9 cases), decreased vision (9 cases), strabismus (4 cases), pain (1 case), floaters (1 case), and no symptoms (2 cases). All of the 26 patients (1 00%) had unilateral sporadic retinoblastoma. Misdiagnosis before referral was common in these older children with active retinoblastoma. Five patients (19%) had prior vitrectomy for presumed vitreous hemorrhage or endophthalmitis while the ret inoblastoma was unsuspected clinically, one patient (4%) had cryotherapy for presumed Coats disease, and one (4%) was observed for 7 months for pre sumed vitreous hemorrhage. The clinician should seriously consider the pos sibility of retinoblastoma in children who present with signs of unexplained vit reous hemorrhage or endophthalmitis, even if they are older than 5 years of age. Ophthalmology 1991; 98:395-399
The incidence of retinoblastoma in the United States varies slightly, depending on the population studied, but it is generally estimated to be approximately 1:15,000 to 1:20,000 live births. 1•2 Overall, retinoblastoma occurs at an average annual incidence of 5.8 per million. 3 In the 0 to 4 years age group, the annual incidence is 10.9 per million, and in those children aged five years and older, the annual incidence of retinoblastoma is 0.6 per million. 3 There are inconsistencies in the literature regarding sur vival with retinoblastoma in these various age groups. 3- 6 Originally received: September 4, 1990. Revision accepted: December 3, 1990. From the Ocular Oncology Service, Wills Eye Hospital, Jefferson Medical College, Thomas Jefferson University, Philadelphia. Presented at the American Academy of Ophthalmology Annual Meeting, Atlanta, OctjNov 1990 Supported by the Ocular Oncology Fund and the Oncology Research Fund, Wills Eye Hospital, Philadelphia, and the Eye Tumor Research Foun dation Incorporated, Gladwyne, Pennsylvania. Reprint requests to Carol L. Shields, MD, Oncology Service, Wills Eye Hospital, Ninth and Walnut Sts, Philadelphia, PA 19107.
The average patient age at diagnosis of retinoblastoma is 24 months in unilateral cases and 13 months in bilateral cases. 7 •8 Almost 90% of all patients with retinoblastoma are diagnosed before the age of 5 years. 8 Several cases of retinoblastoma in patients of more advanced age have been reported. Retinoblastoma has been newly diagnosed in children between the ages of7 and 18 9 - 15 and has been found to occur even in adults of ages 24, 26, 45, 48, and 60 years. 16- 21 Finlay and Byron22 in 1962 reported on a 74-year-old woman with newly diagnosed retinoblastoma. The reason for the development of this tumor at such advanced age is speculative. Some authors believe that the tumor may arise from a reactivated previously un diagnosed spontaneously regressed/arrested retinoblas toma.23 Others have proposed that the persistence of an embryonal retinal cell may contribute to the unusual de velopment of the tumor at such an advanced age. 16 We report on our series of 26 cases of active retino blastoma in children who were older than 5 years of age at the time ofinitial diagnosis. We point out certain unique aspects of this group ofolder patients with retinoblastoma and alert the clinician to the potential atypical presenta tions of this malignancy in older children. 395
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Table 1. Summary of Features of Retinoblastoma in 26 Children Older than 5 Years of Age Patient No.
Age (Yrs)
1 2 3
5.1 5.1 5.1 5.2 5.3 5.3 5.4 5.5 5.6 5.7 5.7 60 6.0 6.6 6.9 7.0 7.5 8.0 8.0 8.3 10.1
4
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
12.0 13.3 16.3 17.0
18.0
Race
Sex
B
F M F M F M F M F M M F F M M M M F F F
w w B w H w w w w w w H w w w w w w B w w w B w w
M F F F M F
Initial Symptoms Strabismus Poor vision Poor vision Strabismus Leukocoria Leukocoria Strabismus Leukocoria Poor vision Leukocoria Strabismus Pain Leukocoria Poor vision None Leukocoria Poor vision Leukocoria Poor vision Leukocoria Poor vision Floaters Poor vision Leukocoria None Poor vision
Prior Treatment/ Presumed Diagnosis None None None PPV/vit hem None None None None None None PPV/vit hem PPV/Vii inflam Observe/vi! heme None None None None None None None Cryotherapy/Coats disease PPVfvit inflam None PPV/vii inflam None None
Tumor Type
Laterality Inheritance
Treatment
Status
Endophytic Endophytic Endophytic Endophytic Diffuse Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Endophytic Exophytic Endophytic Endophytic Endophytic Exophytic
Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic Unilaleral sporadic Unilateral sporadic Unilateral sporadic Unilateral sporadic
Enucleation* Enucleation* Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation• Enucleation Enucleation Enucleation* Enucleation Enucleation Enucleation Enucleation Enucleation Enucleation
Alive Alive Alive Dead Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Dead Alive Alive Alive Alive Alive Dead
Endophytic Endophytic Endophytic Endophytic Endophytic
Unilateral Unilateral Unilateral Unilateral Unilateral
EBRT Enucleation Enucleation' EBRT Enucleation
Alive Dead Alive Alive Alive
sporadic sporadic sporadic sporadic sporadic
B = black; W = white; H = hispanic; PPV = pars plana vitrectomy; vit hem =vitreous hemorrhage; vit inflam = vitreous inflammation; EBRT = external beam radiolherapy. * Supplemenlary external beam radiotherapy and/or chemotherapy given.
PATIENTS AND METHODS
RESULTS
The charts of all patients with the diagnosis of retino blastoma who presented to the Ocular Oncology Service at Wills Eye Hospital between February 1974 and June 1990 were reviewed and computer coded on detailed flowsheets, using the Macintosh program "4th Dimen sion." Those patients who were 5 years of age (60 months) or older at the time of initial diagnosis were selected for further study. Their selected computerized data were evaluated for the patient's age at initial diagnosis, race, sex, initial symptoms, and prior diagnosis and treatment. The laterality and inheritance pattern of the tumor and the method of treatment of the tumor (observation, cryo therapy, photocoagulation, plaque radiotherapy, external beam radiotherapy, enucleation, and chemotherapy) were recorded. The tumor type (endophytic, exophytic, diffuse, or spontaneous regressed/spontaneous arrested) as made both clinically during the examination on the Ocular On cology Service and histopathologically in those eyes that were enucleated was recorded. Follow-up status (alive and well, alive with metastases, dead of metastases, and dead of other causes) was noted.
There were 400 patients with the diagnosis of retino blastoma seen on the Ocular Oncology Service between February 1974 and June 1990. There were 34 (8.5%) pa tients who were 5 years or older at the time of initial diagnosis. Twenty-six of the 34 patients had active reti noblastoma, while eight patients had inactive tumors (re tinoma). The eight cases of inactive retinoma were ex cluded from this study. A complete evaluation of the 26 cases of active retinoblastoma is presented in Table l. The ages of these older patients with active tumors ranged from 5.1 years (61 months) to 18.0 years (216 months). The median age was 6.3 years (76 months) and the mean age was 8.1 years (97 months). Of the 400 patients, 6 (1.5%) were older than lO years of age, and 3 (0.8%) were older than 15 years of age at initial diagnosis. There were 20 white patients (77%), 4 black patients (17%), and 2 Hispanic patients (6% ). Fourteen of the .pa tients were female (54%) and 12 were male (46%). The tumor was unilateral in all 26 cases (100%) and remained unilateral on follow-up examinations in these cases. The retinoblastoma was sporadic (no family history of reti
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Fig I. Patient 24. Left, 16-year-old girl who presented with a hypopyon that was later determined to be an endophytic retinoblastoma after vitrectomy. Right, gross specimen of the enucleated eye in the same patient shows the fluffy, endophytic retinoblastoma.
Fig 2. Patient 13. Six-year-old girl in whom a vitreous hemorrhage de veloped that was observed for resolution and was later found to have an endophytic retinoblastoma. Notice the anterior chamber tumor nodules inferiorly.
noblastoma) in all 26 cases ( 100%). The initial symptoms included poor vision in 9 (35%) cases, leukocoria in 9 (35%) cases, strabismus in 4 (15%) cases, floaters in 1 (4%) case, pain in 1 (4%) case, and no symptoms in 2 (8%) cases. In seven (27%) cases, the tumor was either observed or given some form of treatment while the retinoblastoma was unsuspected (before referral to us). In five of these seven patients, pars plana vitrectomy had been performed for vitreous hemorrhage (2 cases) and presumed vitreous inflammation (3 cases) (Fig 1). In one case, cryotherapy for presumed Coat's disease was performed. In one case, the eye was observed for 7 months for resolution of vit reous hemorrhage of unclear etiology (Fig 2). The other 19 (73%) patients were referred to us before invasive sur gery or prolonged observation. The retinoblastoma tumors showed the following gen eral clinical patterns of growth: primarily endophytic in
22 (85%) cases, primarily exophytic in 3 (12%) cases, and diffuse in 1 (4%) case. The involved eyes were treated with enucleation in 24 (92%) cases and external beam radio therapy in 2 (8%) cases. Five patients (19%) who were managed by enucleation received supplemental external beam radiotherapy and/or chemotherapy because there was tumor invasion of the optic nerve on histopathologic examination ofthe eye (three cases) or they had undergone prior vitrectomy and there was concern that tumor cells could have been disseminated into extraocular tissues (two cases). Of the 26 patients, 4 ( 15%) have died of metastatic retinoblastoma over a mean follow-up period of 5.1 years (range, 0.5 to 13.3 years; median, 5.0 years). The meta static deaths occurred at a mean of 2.4 years (range, 1.0 to 4.7 years; median, 1.9 years) after initial diagnosis. One of these patients, a 5-year-old boy, had been initially managed by pars plana vitrectomy for unexplained vit reous hemorrhage, and another patient, a 10-year-old boy, had been treated with cryotherapy for presumed Coats' disease. The other two cases of metastatic retinoblastoma with death were in a 7-year-old boy who was found to have retrolaminar invasion of the optic nerve after enu cleation and died of metastatic disease despite aggressive chemotherapy and in a 13-year-old girl whose parents declined all treatment until the tumor eventually extended outside the eye. The parents then consented to enucle ation.
DISCUSSION In 1929, Verhoeff18 published the first American report of a histopathologically confirmed retinoblastoma in an adult, a 48-year-old man. In 1943, McCrea24 reported an authentic case of a newly diagnosed retinoblastoma in a 67-year-old patient. In this case, the patient presented with a cataract and vitreous floaters. Later Rasmussen, 19 Rychener, 25 and Mehra 17 reported on older patients with 397
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retinoblastoma who were initially diagnosed at the ages of 48, 33, and 45 years, respectively. All of these patients had atypical presentations such as pain, inflammation, conjunctival chemosis, or glaucoma. Since these initial case reports of retinoblastoma in adults, there have been several other single cases with ages at diagnosis extending up to age 74 years. 9 - 16 •20 - 23 •26 In all of these reported cases of retinoblastoma in older children, the disease was pre sumably sporadic. Retinoblastoma in older patients (older than 5 years of age) may produce atypical symptoms and signs. Most young patients (younger than 5 years of age) with reti noblastoma develop signs of leukocoria or strabismus that are initially noticed by the parents and lead to subsequent eye examination. In this series of older patients (older than 5 years of age) with retinoblastoma, we found the presenting features to be unusual in several respects. It was the child who first noticed the symptoms in 20 of the 24 cases (83%) in which symptoms were present. These included decreased vision in 9 (35%) cases, leukocoria in 9 (35%) cases, strabismus in 4 (15%) cases, floaters in 1 (4%) case, pain in 1 (4%) case, and no symptoms in 2 (8%) cases. The symptoms of decreased vision, floaters, and pain are distinctly unusual for younger children with this intraocular tumor. Atypical signs of retinoblastoma include hypopyon, hyphema, uveitis, endophthalmitis, vitreous hemorrhage, or orbital cellulitis. 9- 11 •14 •26 In our 26 cases of retinoblas toma in older children, several atypical findings of the disease were seen, often leading to misdiagnosis and de layed treatment. Six patients presented with vitreous "in flammation" and/or hemorrhage that obscured the view ofa tumor, and retinoblastoma was not initially suspected. However, many patients presented with more typical findings of leukocoria and strabismus. Stafford and associates28 suggested that these atypical manifestations carry a higher risk of death due primarily to a delay in diagnosis. They found that 15% of 618 cases of histopathologically proven retinoblastoma seen at the Armed Forces Institute of Pathology were initially mis diagnosed clinically. The misdiagnoses included pano phthalmitis, endophthalmitis, uveitis, tuberculosis, sy phylitic uveitis, sympathetic uveitis, nonspecific uveitis, glaucoma, and "pseudoglioma." In our review of lesions referred to us with the diagnosis of retinoblastoma or rule out retinoblastoma we found that toxocariasis, Coats' dis ease, and persistent hyperplastic primary vitreous were the conditions that were most commonly confused clin ically with retinoblastoma (unpublished data). Worsening survival of the patient with retinoblastoma correlates with the presence of orbital or optic nerve in volvement with the tumor.Z 9 One of the four deaths in this series was in a patient who had undergone prior pars plana vitrectomy who likely had orbital involvement. The other metastatic deaths were in a patient initially treated as Coats' disease, a patient with optic nerve invasion from retinoblastoma, and a patient whose parents refused treatment for the child. In a recent report of three patients with retinoblastoma managed with pars plana vitrectomy, 398
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metastases developed in all three patients. 3° Four of the five patients in our study who underwent vitrectomy, however, remain alive and well without metastatic disease at 14.0, 3.5, 2.5, and 1.0 years follow-up. All four patients were treated aggressively: two underwent enucleation with postoperative external beam radiotherapy and/or che motherapy, one was treated only with external beam ra diotherapy, and one had enucleation at the time of vi trectomy elsewhere after intraoperative telephone con sultation with us. Not included in this study was another older child (5 years old) that we recently evaluated with retinoblastoma who was managed by pars plana vitrec tomy for presumed intraocular inflammation that later proved to be retinoblastoma. He was treated aggressively with enucleation, external beam radiotherapy, and che motherapy, but follow-up is only 5 months. Retinoblastoma should be considered in the differential diagnosis of any child with an intraocular mass or less typical manifestations of intraocular inflammation or hemorrhage. This study has clearly shown that active ret inoblastoma can present in children older than 5 years of age and may produce atypical clinical features in such older children. The use of ancillary testing and possibly obtaining opinions by experienced observers may help make the correct diagnosis and avoid unnecessary delays in the diagnosis of these cases of retinoblastoma.
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