Retinoblastoma in older children

Retinoblastoma in Older Children Zeynel A. Karcioglu, MD,a,b Emad B. Abboud, MD,a Saleh A. Al-Mesfer, MD,a Waleed Al-Rashed, MD,a and Delia H. Pilapil, RN, COTa Purpose: Retinoblastoma (RB) is known to present with atypical signs and symptoms in older patients. Our article reviews the clinical and histopathological features of RB encountered in children older than 5 years of age. Methods: A total of 337 consecutive patients with RB were reviewed. Eighteen (5.3%; 10 males, 8 females) who presented after the age of 5 were selected for further analysis of clinical data and histopathological material in this retrospective, non-comparative case series. Results: The age range was from 5 to 12 years (mean age 6.4). Unilateral disease was seen in 14 children, bilateral disease in 4 children. Eleven children were the product of consanguineous marriages. Seven patients had leukocoria; the others presented with signs of uveitis, cellulitis, and/or trauma. Three patients had flat, plaque-like lesions on histopathologic evaluation. Conclusions: Clinical and histopathologic features were atypical in 47% and 21% respectively in the retinoblastoma patients who presented after the age of 5 years. (J AAPOS 2002;6:26-32) orldwide incidence of retinoblastoma (RB) is reported to range from 1 in 15,000 to 35,000 live births per year.1-4 The incidence of RB in Saudi Arabia is estimated to be 1 in 15,000 live births per year.5,6 Although RB has been diagnosed in older children and adults, the average patient age at diagnosis is about 1 year and 2 years in bilateral and unilateral disease, respectively.7-9 Previous studies in Saudi Arabia indicate that 50% of all RB patients present under the age of 2 years, which corresponds with findings of Pendergrass and Davis3 in the US. Other case studies and series of RB in older individuals have been reported.10 The significance is not simply scientific curiosity about the oncogenesis of this tumor at an advanced age; more importantly, RB in older patients usually manifests atypical signs and symptoms referred to as masquerade syndrome,7-11 which may be misleading in diagnosis and management.

W

SUBJECTS AND METHODS This retrospective study included a review of all 337 patients with RB at the Tumor Registry of King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, seen between July 1983 and November 1997. Patients who were 5 years or older at the time of their initial RB diagnosis were

From the King Khaled Eye Specialist Hospital,a Riyadh, Saudi Arabia, and the Tulane University Health Sciences Center,b New Orleans, Louisiana. Supported in part by an unrestricted grant provided by St. Giles Foundation of New York City, New York (Dr Karcioglu). Submitted March 28, 2001. Revisions accepted September 25, 2001. Reprint requests: Zeynel A. Karcioglu, MD, Tulane University Health Sciences Center, Department of Ophthalmology, 1430 Tulane Ave SL 69, New Orleans, LA 70112-2699. Copyright © 2002 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2002/$35.00 ⫹ 0 75/1/120643 doi:10.1067/mpa.2002.120643

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selected and analyzed further. The clinical and histopathological data on these patients were reviewed with particular attention paid to unordinary clinical manifestations for RB and consequent pitfalls in diagnosis and management.

RESULTS The study included 18 children, 10 males (55.6%) and 8 females (44.4%) with RB, 4 of whom had bilateral disease. No family history of RB could be established in any of the cases. Ten patients (55.5%) were diagnosed at the age of 5 years, 2 patients (11.1%) were diagnosed at 6 years of age, 1 patient (5.5%) was diagnosed at 6.5 years of age, and 5 patients (27.7%) were diagnosed between the ages of 7 and 12 years. Seven patients presented with only leukocoria. Two patients presented with leukocoria plus uveitis-like symptoms; 1 of these patients had a history of trauma. Another child came to our attention with leukocoria, strabismus, and hyphema. One patient had a uveitis-like presentation without other symptoms, 1 presented with uveitis symptoms and strabismus, 1 presented with proptosis secondary to extraocular extension of RB, and 1 child was seen for strabismus but had no other complaints. Four patients came in with a complaint of poor vision, 1 of whom was associated with trauma and pseudohypopyon. One of the bilateral cases presented for examination of the fellow eye, at which time the bilateral nature of the disease was established. Another patient with bilateral disease presented at the age of 12 with a large active RB in the left eye and a regressed tumor in the right eye (Table, Case 3). She had aphakia of the left eye and the parents insisted that she underwent cataract surgery at the age of 3 years, at which time there was no evidence of tumor in either eye. Fourteen (63.6%) eyes were enucleated as primary treatment, and 8 (36.4%) eyes were treated by other means (chemotherapy, external beam radiation therapy, I-125 Journal of AAPOS

OS 7 y/m

OU 12 y/f

OS 6 y/m

2

3

4

Eye exam Post seg

Initial diagnosis

Blurred vision OS; VA: 20/20 OD, LP OS; trauma Hx 2 mos IOP: 14 OD, 46 OS ago K: enlarged hazy; AC: 4⫹ cells; rubeosis iridis

Blurred vision; VA: 20-/125 OD; NLP OS; “cataract surgery” IOP: 15 OD, 10 OS; OS at 3 yrs old aphakia OS; normal OD

B-scan: no mass, no Ca††

US

CT

Follow-up

Enucleation OS

No recurrence in 7 yrs; VA: 20/125 OD

Topical steroids; No recurrence in 12 mos pars plana vitrectomy and lensectomy; cytology: Rb cells, enucleation OS, post-op EBRT ⫹ chemo Rx

Topical steroids; No recurrence in AC tap, RB cells; 12 mos enucleation OS; post-op ERBT

Treatment

Old RB with focal Topical antibiotics Lost to f/u Ca††; no distinct and topical ⫹ mass subconjunctival steroids; refused enucleation ⫹ other Rx

Traumatic uveitis

Questionable mass in vitreous OS

B-scan: disorganized globe, no Ca††

Regressed RB OD; B-scan: delineated mass Delineated mass active RB, OS; OS; focal Ca†† OU with Ca†† OS; aphakia OS peripheral Ca†† OD

Regressed RB OD; white mass with vitreous seeds, OS

(After vitrectomy) intraocular tumor with extensive Ca††

WNL; no mass, no Ca††

Imaging

Traumatic uveitis B-scan: total RD with cataract and mild vitreous opacity RD no Ca††

White lesion inferiorly Endophthalmitis VA: 20/20 OD, 20/60 OS; with seeding; IOP: 14 OD, 32 OS; no exophtic mass AC: deep with 4⫹ cells, fluffy white material; K: hazy with white deposits on posterior surface; no rubeosis iridis

Ant seg

No visibility White pupil OS ⫻ VA: 20/23 OD, FC OS; 2 months IOP: 18 OD, 43 OS; ? trauma Hx AC: shallow with 2⫹ cells; dense cataract OS; rubeosis iridis OS 2⫹ APD OS

Blurred vision OS red eye OS

Presenting Sx/History

Ca††, calcification; EBRT, external beam radiation treatment; f/u, follow-up; Hx, history; OD, right eye; OS, left eye; OU, both eyes; Rx, treatment; Sx, symptoms.

OS 11 y/f

Age/Sex

1

Case #

TABLE Features of 4 selected RB patients who presented after the age of 5 years

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FIG 1. (Case 1) Slit-lamp photograph of cornea and anterior chamber with RB involvement. Tumor layering of posterior corneal surface is apparent at slit beam as clusters of partially necrotic, globular RB seeds. Histopathology of tumor deposits is depicted in inset. Arrow points to FNAB needle track.

brachytherapy, and cryotherapy). In 1 patient, both eyes were enucleated. The follow-up period ranged from 0 to 108 months; the mean follow-up time was 48.6 months (SD ⫾ 33.4). Three patients who presented with intraocular inflammation had undergone previous surgical procedures; 2 patients had vitrectomy and lensectomy, and 1 had anterior chamber paracentesis. In all instances, the globes were enucleated and subsequent orbital external beam radiation therapy was given. One of the vitrectomy patients developed recurrent orbital disease and died as a result of disseminated RB. The other 2 patients were alive with no evidence of recurrent disease after the follow-up periods of 12 and 7 months, respectively. Demographic, clinical, and morphologic data of 4 representative patients are summarized (Table). Histopathologic examination was done on 14 enucleated globes and disclosed 3 (21.4%) placoid tumors with diffuse, infiltrative growth pattern. These lesions were well-differentiated with a minimal amount of necrosis and calcification; however, all 3 revealed a considerable amount of seeding with anterior chamber involvement. None of these globes had optic nerve or choroid invasion with RB. The other 11 globes had large tumors with extensive necrosis and focal calcification that filled much of the vitreous cavity. In 8 of 11 eyes with large tumors, RB had invaded the optic nerve to the level of the lamina cribrosa; retrolaminar invasion was present in 3 of these 8 eyes, and the tumor was present at the optic nerve resection margin in 1. In 7 of 11 eyes the choroid was invaded by RB focally; in 1 eye the tumor extended through the full thickness of the eye wall. The examination of the enucle-

ated globes that underwent surgical procedures revealed tumor cells within 1 of the tracts of the vitrectomy site and paracentesis; the other vitrectomy case was negative for tumor cells.

DISCUSSION In addition to the typical symptoms of RB, such as leukocoria and/or strabismus, older children who develop tumors may present with atypical signs masquerading as uveitis, endophthalmitis, and anterior chamber and vitreous hemorrhages with or without neovascularization.10,12-14 Although 10 of our patients presented with leukocoria, only in 7 was leukocoria the sole presenting symptom; the other 11 patients had a variety of other signs to confuse the initial patient evaluation. The first case summarized in the Table represents a good example of the diffuse, flat type of RB usually encountered in older children.12-15 When the tumor is anterior, as was the case in patient 1 (see Table), the anterior chamber involvement can easily mimic intraocular inflammation.16 A very unusual aspect of this case was the nature of the anterior chamber involvement, which often presents as an inferiorly located pseudohypopyon, leaving the rest of the cornea uninvolved; rubeosis iridis may or may not be present. Instead of a flat-topped pseudohypopyon, the inferior part of the anterior chamber contained an aggregate of tumor seeds. Some of the seeds had a pseudocystic appearance caused by central necrosis. In addition, there was a weblike layering of the tumor on the posterior corneal surface (Figure 1). When the patient’s head was moved passively, the tumor seeds moved freely within the anterior chamber, but the appearance of the tumor deposits on the posterior

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FIG 2. (Case 1) Enucleated globe cut at horizontal plane between 4 o’clock and 8 o’clock positions depicting anterior inferior location of plaque-like retinoblastoma covering posterior aspects of ciliary body zonules and lens.

cornea remained unchanged. Tumor layering on the posterior cornea no doubt affected the endothelial cell function and trabecular meshwork, which led to increased intraocular pressure and stromal edema. Some of the haze resolved following treatment with topical steroids, and intraocular pressure was lowered (from 35 mm Hg to 20 mm Hg). Diffuse tumor layering on the posterior corneal surface probably also contributed to tumor cell seeding into the paracentesis tract, as later demonstrated histopathologically (Figure 2). The lack of lenticular opacities and rubeosis iridis indicate rather rapid development of anterior chamber involvement, most likely secondary to anterior vitreous seeding. As has been the trend in a majority of the reported cases of infiltrating RB, our patients also had unilateral, sporadic tumor with a negative family history.12 The examination of the gross specimen of this case revealed an anterior placoid RB (Figure 3). Histopathologically, this tumor showed minimal necrosis and no calcification. The second and fourth cases are good examples of pseudotrauma syndrome, which mimics subacute anterior chamber inflammation (keratic precipitates, rubeosis, iritis, cataract), and retinal detachment with subretinal fluid. There was no blood within the anterior chamber in our patients, although presence of hyphema has been reported to further complicate the situation.14 Spontaneous intravitreal or subretinal bleeding in untreated RB is rare and confuses the differential diagnosis. In Case 2 (see Table),

pars plana lensectomy and vitrectomy were initiated, but the procedure was discontinued when whitish, thick fluid containing tumor was encountered (Figure 4). In many questionable trauma cases, the ophthalmologist does not have the luxury of direct visualization of the fundus and must rely on imaging procedures. In this case, the diagnostic difficulty was due to misleading B-scan, which failed to reveal a mass lesion and calcification, and the unavailability of computerized tomography and magnetic resonance imaging prior to the decision to perform an invasive procedure. The history of eye trauma in this 7 year-old boy further compounded the diagnostic dilemma. When ultrasonography is performed for this purpose, it is best that standardized echography (A- and B-scans together) be employed. If there is a question regarding calcification within the lesion, it should be further investigated with lower tissue gain. Small calcifications within RB are seen as reflective echoes, even at sensitivity levels of 30-40 decibels.17 Furthermore, if ever there is a question of differentiating vitreal or subretinal hemorrhage or fluid accumulation from a tumor mass, magnetic resonance studies offer the best differentiation between neoplastic lesion and exudates within the eye.18 It is interesting to note than none of the patients in our series presented with RB-associated orbital inflammation, another well- known masquerade syndrome. This is in agreement with a previously reported large series.10 Al-

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FIG 3. (Case 1) Histopathologic appearance of paracentesis track (arrowhead ) and thin layering of RB on posterior corneal surface (H&E, original magnification: ⫻100).

though Shields et al10 mention orbital cellulitis-like presentation in their discussion, none of their patients was reported to have orbital cellulitis at initial evaluation. In our experience with 14 patients who presented with RBassociated orbital inflammation, the mean age was 17.6 months, and the oldest patient was 30 months old when first seen.14 Although we agree that orbital cellulitis-like disease is an unusual presentation of RB in our experience, it is not frequently encountered in the older age group.

Case 3 (see Table) was a 12-year-old girl who presented with active and regressed RB in OS and OD, respectively (Figure 5). She had never been diagnosed or treated as RB until she was seen by us. It is not rare to encounter regressed, calcified RB in older children and adults; however, its presentation with active disease in the fellow eye at this age was unusual. It is reported that RB diagnosed in older children has a poorer prognosis, primarily due to the delay in diagnosis

FIG 4. (Case 2) Cytology preparation from vitrectomy fluid showing RB cell clusters (arrowheads) mixed with hemolyzed erythrocytes and inflammatory cells (H&E, original magnification: ⫻400).

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FIG 5. (Case 3) Funduscopic photograph of spontaneously regressed RB in right eye. Photograph was taken at patient’s presentation with exophytic RB in left eye at age of 12.

and treatment.19 Stafford et al19 report 18% of histologically proven RB cases were misdiagnosed clinically as intraocular inflammation, sympathetic ophthalmia, tuberculosis, etc. This study was done in the 1960s, when 18% seemed a reasonable rate for clinical misdiagnosis of RB; with today’s advanced diagnostic techniques, the percentage is probably closer to 5%.19 Tumor seeding along the tracts of biopsy needles and vitrectomy instruments is also reported.20-22 It appears that the numbers of inadvertent vitrectomy in RB patients is increasing because of popular use of diagnostic vitrectomy and retinal biopsy in the diagnostic work-up of uveitis patients.23 Many examples of extraocular extension of RB following intraocular surgery associated with secondary orbital disease are present in the literature.24 Invasive procedures, including fine needle aspiration biopsy and anterior chamber paracentesis, are potentially dangerous and should be avoided unless absolutely unavoidable. When intraocular surgery is performed in eyes subsequently found to have RB, enucleation followed by orbital radiation with or without chemotherapy should be implemented as soon as possible. References 1. Francois J, Mafton Van Leuven MT. Recent data on the hereditary of retinoblastoma. In: Boniuk M, editor. Ocular and Adnexal Tumors, New and Controversial Aspects. St. Louis, Mo: Mosby; 1964. p. 23-41. 2. Sanders BM, Draper GJ, Kingston JE. Retinoblastoma in Great Britain 1969-80: incidence, treatment, and survival. Br J Ophthalmol 1988;72:576-83. 3. Pendergrass TW, Davis S. Incidence of retinoblastoma in the United States. Arch Ophthalmol 1980;98:1204-10.

4. Duvea SS. The incidence of retinoblastoma. Am J Ophthalmol 1975; 80:263-5. 5. Mullaney PB, Karcioglu ZA, Al-Mesfer SA, Dowaidi M. Retinoblastoma referral patterns in Saudi Arabia. Ophthalmic Epidemiol 1996; 3:35-46. 6. Al-ldrissi I, Al-Kaff AS, Senft SH. Cumulative incidence of retinoblastoma in Riyadh, Saudi Arabia. Ophthalmic Paediatr Genet 1992; 13:9-12. 7. Binder PS. Unusual manifestations of retinoblastoma. Am J Ophthalmol 1974;77:674-9. 8. Takahashi T, Tamura S, Inoue M, Isayama Y, Sashikata T. Retinoblastoma in a 26-year-old adult. Ophthalmology 1983;90:179-83. 9. Rubenfeld M, Abramson DH, Ellsworth RM, Kirchin FD. Unilateral versus bilateral retinoblastoma: Correlations between age at diagnosis and stage of ocular disease. Ophthalmology 1986;93: 1016-9. 10. Shields CL, Shields JA, Shah P. Retinoblastoma in older children. Ophthalmology 1991;98:395-9. 11. Labib MAM, EL-Gammal Y, El-Aguizy H. Retinoblastoma: unusual presentation. Bull Ophthalmol Soc Egypt 1975;68:385-9. 12. Shields JA, Shields CL, Eagle RC, Blair CJ. Spontaneous pseudohypopyon secondary to diffuse infiltration retinoblastoma. Arch Ophthalmol 1998;106:1301-2. 13. Haik BG, Dunleavy SA, Cooke C, Ellsworth RM, Abramson DH, Smith ME, et al. Retinoblastoma with anterior chamber extension. Ophthalmology 1987;94:367-70. 14. Karcioglu ZA, Al-Mesfer SA, Huaman AM, Mullaney PB. Orbital cellulitis with retinoblastoma: review of 14 cases. Invest Ophthalmol Vis Sci 1997;38:Sl22. 15. Nicholson DH, Norton EW. Diffuse infiltrating retinoblastoma. Trans Am Ophthalmol Soc 1980;78:265-89. 16. Shields JA, Shields CL. Ocular tumors. A text and atlas. Philadelphia, Pa: Saunders; 1992. p. 311-12. 17. Shields JA, Leonard BC, Michelson JB, Sarin LK. B-scan ultrasonography in the diagnosis of atypical retinoblastomas. Can J Ophthalmol 1976;11:42-51. 18. Beets-Tan RG, Hendriks MJ, Ramos LM, Tan KE. Retinoblastoma: CT and MRI. Neuroradiology 1994;36:59-62.

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19. Stafford WR, Yanoff M, Parnell BL. Retinoblastomas initially misdiagnosed as primary ocular inflammations. Arch Ophthalmol 1969; 82:771-3. 20. Rodriguez A. Diagnosis of retinoblastoma by cytologic examination of the aqueous and the vitreous. Modern Problems Ophthalmol 1977;:142-8. 21. Karcioglu ZA, Gordon RA, Karcioglu GL. Tumor seeding in ocular fine needle aspiration biopsy. Ophthalmology 1985;92:1763-7.

Journal of AAPOS Volume 6 Number 1 February 2002 22. Finger P, Harbour W, Karcioglu ZA. Metastatic retinoblastoma. Survey Ophthalmol 2001(in press). 23. Shields CL. Vitrectomy for unsuspected retinoblastoma. 10th International Congress of Ocular Oncology. Abstract Book. Amsterdam, The Netherlands, 2001, p. 229. 24. Stevenson KE, Hungerford J, Garner A. Local extraocular extension of retinoblastoma following intraocular surgery. Br J Ophthalmol 1989;73:739-42.