Saudi Journal of Ophthalmology
Volume 25, Issue 2 , Pages 159-167, April 2011

Orbital retinoblastoma: Present status and future challenges – A review

Ocular Oncology Service, L.V. Prasad Eye Institute, Road No. 2, Banjara Hills, Hyderabad 500034, India

Received 24 September 2010; accepted 6 October 2010.

Article Outline

Abstract 

Orbital retinoblastoma is a catastrophic event traditionally carrying a dismal prognosis. Although its incidence is less in the developed countries it continues to be one of the major diagnosis at presentation in the developing world. Orbital retinoblastoma encompasses a wide range of distinct clinical entities with varying tumor load. There are no standard treatment protocols as of now but the current preferred management is multimodal with a combination of initial high-dose chemotherapy, surgery, external beam radiotherapy and prolonged chemotherapy for twelve cycles. In spite of progress on all fronts including surgical, medical, diagnostic, genetic and rehabilitative with improving survival rates, however, lack of access to medical facilities, lack of education about the need for early medical attention and cultural resistance to enucleation continue to contribute to an epidemic of extra ocular disease at diagnosis in the developing world. This review introduces the various terminologies used in the spectrum of orbital retinoblastoma, discusses in details the clinical aspects and management protocols, current status and the future directions.

Keywords: Retinoblastoma, Orbit, Extra ocular, Chemotherapy, Radiotherapy, Proptosis

 

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1. Introduction 

Retinoblastoma is the most common intraocular malignancy in children, with a reported incidence ranging from 1 in 15,000 to 1 in 18,000 live births (Bishop and Madsen, 1975). It is bilateral in about 25–35% of cases (Shields, 1992). The average age at diagnosis is 18months, unilateral cases being diagnosed at around 24months and bilateral cases before 12months (Shields, 1992). Retinoblastoma was associated with near certain death just over a century ago. Early tumor recognition aided by indirect ophthalmoscopy and refined enucleation technique contributed to an improved survival from 5% in 1896 to 81% in 1967. Advances in external beam radiotherapy in the 1960s and 1970s, resulted in further substantial eye salvage (Shields, 1992).

The recent advances like identification of genetic mutations, replacement of external beam radiotherapy by chemoreduction as the primary management modality, use of chemoreduction to minimize the size of regression scar with consequent optimization of visual potential, identification of histopathologic high risk features following enucleation and provision of adjuvant therapy to reduce the incidence of systemic metastasis, protocol based management of retinoblastoma with accidental perforation or intraocular surgery and aggressive multimodal therapy in the management of orbital retinoblastoma have contributed to improved outcomes in terms of better survival, improved eye salvage and potential for optimal visual recovery.

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2. Present status 

In neglected or untreated cases retinoblastoma can demonstrate extra ocular spread primarily through the optic nerve (Magramm et al., 1989) and also through the sclera (Rootman et al., 1978). Though it is a rare clinical presentation in developed countries ranging from 6.3% to 7.6% (Grabowski and Abramson, 1987, Ellsworth, 1974), it is not an unusual feature in developing and under developed world. Leal-Leal et al. (2004) reported an incidence of 18% in a large multi-center study from Mexico. Kao et al. (2002) from Taiwan reported the incidence of orbital retinoblastoma to be 36% in a large study. The incidence is even higher around 40% from Nepal where Badhu et al. (2005) reported proptosis to be the most common presenting feature of retinoblastoma.

Orbital retinoblastoma is one of the major contributors to mortality and carries a poor prognosis for life. (Stannard et al., 1979, Hungerford, 1993, Finger et al., 2002, Abramson et al., 2003, Schvartzman et al., 1996). The presence of orbital invasion is associated with 10 to 27 time’s higher risk of metastasis when compared to cases without orbital extension (Singh et al., 2000, Kopelman et al., 1987, Khelfaoui et al., 1996).

The 5year survival rates of orbital retinoblastoma have been reported to be 88% from United Kingdom (Sanders et al., 1988), 91% from Japan (Anonymous, 1992) and 93% from United States (Abramson et al., 1994, Young et al., 1999). However, the mortality in developing countries is still high owing to late presentations compounded by socio-economic factors with the mortality reported as high as 50–90% (Badhu et al., 2005, Schvartzman et al., 1996, Ajaiyeoba et al., 1993, Chantada et al., 1999, Kodilinye, 1967).

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3. Classifications 

Orbital retinoblastomas have been variously classified. Childrens Cancer Group (CCG) classification criteria (Wolff et al., 1978) (Table 1) and classification based on the clinicopathological presentations (Honavar, 2007) (Table 2) are used.

Table 1. Childrens cancer group classification of orbital retinoblastoma.
ClassFeature
Class IMicroscopic involvement of scleral emissaries
Class IIMicroscopic involvement of cut end of optic nerve
Class IIIOrbital disease in the biopsy
Class IVCNS disease with brain mass or CSF with positive tumor cells
Class VBlood borne metastasis to bone marrow, bone or lymphatic metastasis to lymph nodes
Table 2. Clinicopathological Classification of Orbital Retinoblastoma.
1Primary orbital retinoblastoma
2Secondary orbital retinoblastoma
3Accidental orbital retinoblastoma
4Overt orbital retinoblastoma
5Microscopic orbital retinoblastoma

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4. Clinical presentations 

4.1. Presenting Age 

It is well known that orbital retinoblastomas manifest commonly due to late presentations. The average age at diagnosis is 18months (Shields, 1992). In contrast to this Menon et al. (2000) reported the average age at diagnosis to be 30months for orbital retinoblastoma whereas Doz et al. (1995) and Antoneli et al. (2003) reported it as 38 and 32.9months respectively.

4.2. Most common presenting feature 

The most common presenting sign or symptom was leukokoria in the Antoneli et al. (2003) (68%) in comparison to Menon et al. (2000) where it was reported to be 72%. But in the Menon et al. (2000) series proptosis was the most common presenting sign (83%). The rate of proptosis as the most common presenting sign was 75.9% versus 24.1%, in patients with unilateral and bilateral disease.

4.3. Primary orbital retinoblastoma 

This refers to a clinically or radiologically detected orbital extension of an intraocular retinoblastoma at the initial presentation, with or without proptosis or a fungating mass. Silent proptosis with manifest intraocular tumor is the usual presentation (Fig 1a and b). Proptosis with inflammation generally indicates reactive sterile orbital cellulitis secondary to intraocular tumor necrosis. Palpable orbital mass (Fig. 2) , eyelid swelling or an exuberant fungating orbital mass (Fig. 3) are other manifestations (Honavar, 2007).

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  • Figure 1. 

    (a and b). Bilateral advance retinoblastoma. Left eye gross proptosis and right eye anterior segment seeding can be appreciated. (a) CT Scan axial cuts of the same patient confirmed orbital mass and gross optic nerve extension (b).

4.4. Secondary orbital retinoblastoma 

This refers to orbital recurrence following an uncomplicated enucleation for intraocular retinoblastoma. Orbital recurrence may present between weeks to years after the primary surgery. Unexplained displacement, bulging or extrusion of a previously well fitting conformer or prosthesis is a characteristic finding. Secondary orbital retinoblastomas may also present as a conjunctival nodule (Honavar, 2007).

Orbital recurrence of retinoblastoma after enucleation usually carries poor prognosis with reported rates of mortality being as high as 94–100% (Hungerford et al., 1987, Reese, 1963). Distant relapse was found to be the commonest cause of mortality (Reese, 1963).

4.5. Accidental orbital retinoblastoma 

This refers to inadvertent perforation, fine needle aspiration biopsy or intraocular surgery in an eye with unsuspected intraocular retinoblastoma (Honavar, 2007).

4.6. Overt Orbital Retinoblastoma 

This refers to previously unrecognized extrascleral or optic nerve extension discovered during enucleation. A pale pink episcleral nodule or an enlarged and inelastic optic nerve are indicators of overt orbital retinoblastoma that needs to be recognized during enucleation (Honavar, 2007). The prognosis can be dismal if these cases are not managed carefully.

4.7. Microscopic Orbital Retinoblastoma 

This refers to retinoblastomas with full thickness scleral infiltration, extrascleral extension or invasion of the optic nerve on histopathologic evaluation of an enucleated eye for intraocular retinoblastoma (Fig. 4). There may not be any clinically evident orbital extension of retinoblastoma (Honavar, 2007). These high risk histopathologic features have a strikingly higher incidence in developing countries as compared to the published data from the developed countries (Magramm et al., 1989, Kopelman et al., 1987, Khelfaoui et al., 1996, Messmer et al., 1989, Shields et al., 1994) as demonstrated by Vemuganti et al. (2000). In this series 46% of the 76 eyes enucleated for advance retinoblastoma in India had optic nerve invasion at or beyond lamina cribrosa and 7% had scleral infiltration or extrascleral extension. This could also partly contribute to the high incidence of orbital retinoblastoma in developing countries.

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5. Investigations 

A careful and detailed evaluation of the patient is mandatory. Apart from the routine clinical work up, regional lymph nodes need to be palpated and a fine needle aspiration biopsy should be done if found to be involved. Imaging modality of choice is MRI of orbits and brain. Alternatively a CT Scan can also be performed to confirm the presence of orbital retinoblastoma.(Fig. 5a and b) A metastasis work up involves bone marrow biopsy and cerebrospinal fluid cytology. Whole body bone scans using technetium-99 as shown by Kiratli et al. (1998) and Flourine-18 flourodeoxyglucose positron emission tomography (PET CT) as demonstrated by Moll et al. (2004) may pick up early metastasis. Biopsy can be done in those cases where the primary diagnosis or histopathology is unavailable.

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  • Figure 5. 

    (a and b). CT Scan axial cuts show gross left optic nerve thickening of the tumor measured radiologically (a) CT Scan axial cuts show gross left optic nerve extension along with intracranial extension (b).

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6. Treatment 

6.1. Primary orbital retinoblastoma 

There are no proven definitive therapy or management protocols for orbital retinoblastoma. They continue to remain a challenging disease to treat because of its complex nature and usually various combination therapies are needed to achieve reasonable results. White (1991) has discussed the use of chemotherapeutic agents including cyclophosphamide, teniposide, cisplatin, vincristine, doxorubicin in conjunction with external beam radiotherapy. Menon et al. (2000) and Doz et al. (1995) have shown encouraging results with the use of etoposide in the management protocols. Acquaviva et al. (1982) favoured a combination of chemotherapy with radiotherapy. On the other hand (Antoneli et al., 2003) showed no benefit from aggressive chemotherapy alone. Goble et al. (1990) showed good long term survival with multimodal therapy.

6.1.1. Why do we need multimodal therapy ? 


(a)Systemic chemotherapy alone is unlikely to eradicate residual orbital disease (Antoneli et al., 2003, Doz et al., 1994).

(b)Orbital exenteration alone is unlikely to achieve surgical clearance (Hungerford et al., 1987, Reese, 1963).

(c)External beam radiotherapy is unlikely to prevent systemic metastasis (Amendola et al., 1990, Scott et al., 1999).

(d)Histopathologic evidence of viable tumor cells even in phthisical eyes following neoadjuvant chemotherapy (Ali et al., 2009).

Based on the current evidence as mentioned above Honavar and Singh (2005) developed a treatment protocol comprising of initial triple drug high-dose chemotherapy (3–6 cycles) followed by appropriate surgery, orbital radiotherapy and an additional 12 cycle standard dose chemotherapy. Detailed protocol is listed in Table 3.

Table 3. Suggested protocol for primary orbital retinoblastoma.
Baseline investigations
CT Scan or Magnetic resonance imaging
Bone marrow biopsy
Cerebrospinal fluid cytology
Treatment
Initial Chemotherapy–High dose triple-drug chemotherapy for 3–6 cycles every three weeks.
Surgery–Enucleation
Assessment of orbital tumor by imaging after completion of third cycle. If resolved than proceed with enucleation. If unresolved give additional 3 cycles of chemotherapy.
Assessment of orbital tumor after completion of 6 cycles. If resolved proceed with enucleation and if not proceed with exenteration.
Radiotherapy–45–50Gy in fractionated doses to the orbit.(External beam)
Subsequent chemotherapy–Continuation of high-dose chemotherapy for 12 cycles
Follow-up investigations
Imaging at 12, 18, 24 and 36months. Bone marrow biopsy and cerebrospinal fluid cytology at 6, 12, 18, 24 and 36months.
High-dose chemotherapy (mg/kg body weight)
Vincristine–Day 1–0.025mg/kg
Etoposide–Day 1–12mg/kg
–Day 2–12mg/kg
Carboplatin–Day 1–28mg/kg

In this series six cases of orbital retinoblastoma without intracranial extension and systemic metastasis underwent the protocol as described above and the authors reported dramatic resolution of orbital involvement and a mean event-free survival of 36months. Most of the eyes following chemotherapy become phthisical (Fig. 6a and b). The authors agreed that their encouraging protocol needs validation and further studies are needed to know whether fewer cycles are as equally effective since there are concerns of the long term effects of high-dose chemotherapy.

6.2. Secondary orbital retinoblastoma 

Hungerford et al. (1987) and Reese (1963) have reported dismal results and poor prognosis for cases of orbital recurrences. None of the 25 cases reported by Reese et al. survived. Most of the deaths occur within two years. The point to be taken into account in these series was the lack of multimodal approach. In contrast Goble et al. (1990) demonstrated long term survival with local surgical excision, orbital radiotherapy and systemic chemotherapy. Antoneli et al. (2003) reported encouraging results from multimodal approaches but were not supportive of aggressive chemotherapy. Based on the increasing literature support for a multimodal therapy (Honavar and Singh, 2005) proposed a protocol (Table 3) that is currently under investigation for the management of secondary orbital retinoblastoma with very encouraging early results. However long term results of all the current multimodal protocols need to be reviewed before definite protocols can be formulated in future.

6.3. Accidental orbital retinoblastoma 

Eyes with retinoblastoma undergoing enucleation deserves special considerations (Honavar, 2007):

(a)All efforts should be taken to prevent accidental perforation.

(b)It is preferable to avoid applying traction sutures at the insertion of extra ocular muscles to avoid perforation.

(c)Hemostats applied to muscle stumps provide adequate traction.

(d)Retinoblastoma with sterile orbital cellulitis should be adequately treated to reduce the inflammation before enucleation.

Eyes with retinoblastoma which underwent inadvertent intraocular surgery should immediately undergo an extended enucleation that additionally includes the conjunctiva overlying the entry points or over the ports with a 4mm margin all around (Shields et al., 2000). In cases where prompt enucleation is not possible all such entry points or ports should be subjected to triple freeze–thaw cryotherapy followed by enucleation as appropriate. All such eyeballs merit special histopathologic analysis for high risk features and specific analysis of the entry wounds for the presence of tumor cells. Metastasis work up in the form of bone marrow biopsy and cerebrospinal fluid analysis for the presence of tumor cells is mandatory. Following enucleation, it is recommended to subject the patients to orbital external beam radiotherapy and 12 cycles of high-dose chemotherapy (Shields et al., 2000).

6.4. Overt orbital retinoblastoma 

Extra ocular extension suspected during surgery deserves special considerations.

(a)If an extra-scleral lesion is visible, it should be completely excised along with the overlying tenon’s capsule during enucleation (Honavar and Singh, 2005).

(b)The surgeon should aim at an optic nerve length of 15mm. In case due to unforeseen circumstances the length of the optic nerve obtained is less than 10 mms when it is suspected to be involved due to increased thickness or inelasticity, Honavar (2007) preferred to explore the orbit and attempt an additional optic nerve length during the same sitting.

(c)Biointegrated implants should be avoided in suspected cases of orbital retinoblastoma as there is possibility of implant exposure due to subsequent external beam radiotherapy.

All cases of overt orbital retinoblastoma undergo metastasis work up in the form of bone marrow biopsy and cerebrospinal fluid analysis for the presence of tumor cells. Following enucleation, it is recommended to subject the patients to orbital external beam radiotherapy and 12 cycles of high-dose chemotherapy (Shields et al., 2000).

Chantada et al. (2003) in an exclusive study of overt orbital retinoblastoma using a multimodal approach has shown 5year event-free survival rates to be 84% in a group of 15 patients.

6.5. Microscopic orbital retinoblastoma 

Several studies have now identified high risk factors for extra ocular recurrences to be post-laminar optic nerve involvement, invasion of optic nerve transection, massive choroidal invasion, scleral infiltration and even anterior chamber involvement (Magramm et al., 1989, Stannard et al., 1979, Schvartzman et al., 1996, Khelfaoui et al., 1996, Uusitalo et al., 2001, Honavar et al., 2002). The patients where the tumor involved the cut end of optic nerve, scleral or extrascleral involvement are recommended to undergo external beam radiotherapy followed by 12 cycles of high-dose chemotherapy. (Honavar and Singh, 2005).

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7. Glimpse of the future and its challenges 

When reviewing the literature one fact that stands out clearly is the increasing survival of patients with orbital retinoblastoma. Progress has been made and is continuing on all fronts including surgical, medical, diagnostic, genetic and rehabilitative (Shields and Shields, 2010, Bakhshi et al., 2010).

Multimodal therapies for advanced retinoblastoma are picking up pace and support from all spheres as amply elucidated in this review. Histopathologic evaluations of eyes following neoadjuvant chemotherapy for orbital retinoblastoma have further vouched for multimodal approaches (Ali et al., 2009). The introduction of stem cell rescue along with high-dose chemotherapy has added another dimension to the treatment of orbital retinoblastoma (Kremens et al., 2003, Lee et al., 2008). The Children’s Oncology Group trials (COG trials) currently undergoing have made a great effort to standardize the treatment protocols worldwide. Their well designed COG ARET 0321 trial of intensive multimodal therapy for extra ocular retinoblastoma will probably lay to rest most of the confusion revolving around management protocols.

Advances in external beam radiotherapy for retinoblastoma with more precise control of the beam through better collimation and tighter isodose curves strongly argue its continuing supportive role in the management. The modern approaches that are being investigated include stereo tactic conformal radiotherapy using a micromultileaf collimator, proton therapy using a fixed horizontal beam and tantalum localization or a rotating gantry with spot scanning (Munier et al., 2008). Better survival has led to increasing research in newer implants with focus on orbital development and hence better cosmesis.

On the diagnostic front exploring the fetal eye is a new frontier. Fetal Magnetic resonance imaging (MRI) and fetal three-dimensional ultrasound are being increasingly explored for prenatal diagnosis. The only two cases reported of in utero diagnosis using fetal ultrasound had massive extra ocular extension (Maat-Kevit et al., 1993, Salim and Wiknjosastro, 1998). Whole body bone scans using technetium-99 as shown by Kiratli et al. (1998) and Flourine-18 flourodeoxyglucose positron emission tomography (PET CT) as demonstrated by Moll et al. (2004) reflect a glimpse of what possibly lies in store for early detection of metastasis.

On the genetic front there has not been a great progress inspite of the fact that RB1 was the first human cancer gene to be cloned. Development of an automated, inexpensive screening examination for RB1 mutations has been a long term need. However recently Parsam et al. (2009) from the authors group have developed and published a combinatorial and less expensive approach for the detection of RB1 mutations which is likely to have applications as a screening tool. Ali et al. (2010) have for the first time explored the possible correlations between different types of mutations on the RB1 gene and clinical presentations. It is interesting to note that large deletions were found to correlate with extra ocular extension and metastasis at presentation. Further efforts are needed to make it a routine part of patient care.

On the social front awareness through education and outreach to the community has helped to prevent delayed presentations and an early referral. Impact of educational programmes in certain developing nations of Central America where it was linked with the vaccination programmes is continuing to yield encouraging results with the rate of orbital retinoblastoma diagnosis reducing by almost half in the post-campaign period (Leander et al., 2007, Wilimas et al., 2009). Similar programmes could be cloned to developing countries in Africa and Southern Asia specifically targeting the education of general population and primary care providers.

Lastly other areas being investigated include pharmacologic enhancement of radiotherapy, use of tumor cell targeting techniques, differentiating agents, immunotherapy and employing metastasis suppressor genes to prevent metastasis. (White, 1991, Kauffman et al., 2003).

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8. Conclusions 

Orbital retinoblastoma still stands as a tall challenge requiring multi-modal and multi-disciplinary approach. The Childrens Oncology Group trial for extra ocular retinoblastoma is likely to formulate an effective and standardized management protocol in the near future. Although the survival has increased over the last few years, lack of access to medical facilities, lack of education about the need for early medical attention and cultural resistance to enucleation continue to contribute to an epidemic of extra ocular disease at diagnosis in the developing world. The goals for the future need to be well designed, implemented and spread over medical, socio-economic and research frontiers.

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References 

  1. Abramson DH, Niksarli K, Ellsworth RM, et al. Changing trends in the management of retinoblastoma 1951–1965 vs 1966–1980. J. Pediatr. Ophthalmol. Strabismus. 1994;31:32–37
  2. Abramson DH, Beaverson K, Sangani P, et al. Screening for retinoblastoma: presenting signs as prognosticators of patient and ocular survival. Paediatrics. 2003;112:1248–1255
  3. Acquaviva A, Barberi L, Bernardini C, et al. Medical therapy of retinoblastoma in children. J. Neurosurg. Sci. 1982;26:49–52
  4. Ajaiyeoba IA, Akang EE, Campbell OB, et al. Retinoblastomas in Ibadan: treatment and prognosis. West Africa J. Med. 1993;12:223–227
  5. Ali, M.J., Gupta, R., Vemuganti, G.K., Honavar, S.G., 2009. Histopathology of retinoblastoma after primary chemotherapy. In: Proceedings of the XIV International Congress of Ocular Oncology, Cambridge, p. 296.
  6. Ali MJ, Parsam VL, Honavar SG, et al. RB1 gene mutations in retinoblastoma and its clinical correlation. Saudi J. Ophthalmol. 2010;24:119–123
  7. Amendola BE, Lamm RF, Markoe AM, et al. Radiotherapy of retinoblastoma. A review of 63 children treated with different irradiation techniques. Cancer. 1990;66:21–26
  8. Anonymous, 1992. Survival rate and risk factors for patients with retinoblastoma in Japan. The committee for the National Registry of Retinoblastoma. Jpn. J. Ophthalmol., 36, 121–131.
  9. Antoneli CB, Steinhorst F, de Cassia Braga RK, et al. Extra ocular retinoblastoma a 13-year experience. Cancer. 2003;98:1292–1298
  10. Badhu B, Sah SP, Thakur SK, et al. Clinical presentation of retinoblastoma in Eastern Nepal. Clin. Exp. Ophthalmol. 2005;33:386–389
  11. Bakhshi S, Meel R, Mohanti BK, et al. Treatment and outcomes of non-metastatic extra-ocular retinoblastoma with uniform chemotherapy protocol. J. Pediatr. Hematol. Oncol. 2010;32:42–45
  12. Bishop JO, Madsen EC. Retinoblastoma review of current status. Surv. Ophthalmol. 1975;19:342–366
  13. Chantada G, Fadino A, Manzitti J, et al. Late diagnosis of retinoblastomas in a developing country. Arch. Dis. Child. 1999;80:171–174
  14. Chantada G, Fadino A, Casak S, et al. Treatment of overt extra-ocular retinoblastoma. Med. Pediatr. Oncol. 2003;40:158–161
  15. Doz F, Khelfaoui F, Mosseri V, et al. The role of chemotherapy in orbital involvement of retinoblastoma. The experience of single institution with 33 patients. Cancer. 1994;74:722–732
  16. Doz F, Neuenschwaner S, Plantaz D, et al. Etoposide and carboplatin in retinoblastomas a study by the Societe Francaise d’Oncologie Pediatrique. J. Clin. Oncol. 1995;13:902–909
  17. Ellsworth RM. Orbital Retinoblastoma. Trans. Am. Ophthalmol. Soc. 1974;72:79–88
  18. Finger PT, Harbour JW, Karcioglu ZA. Risk factors for metastasis in retinoblastoma. Surv. Ophthalmol. 2002;47:1–16
  19. Goble RR, Mckenzie J, Kingston JE, et al. Orbital recurrence of retinoblastoma successfully treated by combined therapy. Br. J. Ophthalmol. 1990;74:97–98
  20. Grabowski EF, Abramson DH. Intraocular and extra ocular retinoblastoma. Hematol. Oncol. Clin. North. Am. 1987;1:721–735
  21. Honavar, S.G., 2007. Orbital Retinoblastoma. In: Singh, A.D., Damato, B.E., Pe’er, J., et al. (Eds.), Clinical Ophthalmic Oncology, first ed., Saunders Elsevier, pp. 477–483.
  22. Honavar SG, Singh AD. Management of advanced retinoblastoma. Ophthalmol. Clin. North. Am. 2005;18:65–73
  23. Honavar G, Singh A, Shields C, et al. Post enucleation adjuvant therapy in high risk retinoblastoma. Arch. Ophthalmol. 2002;120:923–931
  24. Hungerford J. Factors influencing metastasis in retinoblastoma. Br. J. Ophtalmol. 1993;77:541
  25. Hungerford JL, Kingston JE, Plowman PN. Orbital recurrence of retinoblastoma. Ophthalmic. Pediatr. Genet. 1987;8:63–68
  26. Kao LY, Su WW, Lin YW. Retinoblastoma in Taiwan: survival and clinical characteristics 1978–2000. Jpn. J. Ophthalmol. 2002;46:577–580
  27. Kauffman EC, Robinson VL, Stadler WM, et al. Metastasis Suppression: the Evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site. J. Urol. 2003;169:1122–1133
  28. Khelfaoui F, Validire P, Auperin A, et al. Histopathologic risk factors in retinoblastoma a retrospective study of 172 patients treated in a single institution. Cancer. 1996;77:1206–1213
  29. Kiratli PO, Kiratli H, Ercan MT. Visualization of orbital retinoblastoma with technetium-99m (V) dimercaptosuccinic acid. Ann. Nucl. Med. 1998;12:157–159
  30. Kodilinye HC. Retinoblastoma in Nigeria: problems of treatment. Am. J. Ophthalmol. 1967;63:469–481
  31. Kopelman JE, McLean IW, Rosenberg SH. Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmology. 1987;94:371–377
  32. Kremens B, Wieland R, Rienhart H, et al. High dose chemotherapy with autologous stem cell in children with retinoblastoma. Bone Marrow Transplant. 2003;31:281–284
  33. Leal-Leal C, Flores-Rojo M, Medina-Sanson A, et al. A multi-centre report from the Mexican retinoblastoma group. Br. J. Ophthalmol. 2004;88:1074–1077
  34. Leander C, Fu LC, Pena A. Impact of an education programme on the late diagnosis of retinoblastoma in Honduras. Pediatr. Blood Cancer. 2007;49:817–819
  35. Lee SH, Yoo KH, Sung KW, et al. Tandem high-dose chemotherapy and autologous stem cell rescue in children with bilateral advanced retinoblastoma. Bone Marrow Transplant. 2008;42:385–391
  36. Maat-Kevit JA, Oepkes D, Hartwing NG, et al. A large retinoblastoma detected in a fetus at 21 weeks of gestation. Prenat. Diagn. 1993;13:377–384
  37. Magramm I, Abramson DH, Ellsworth RM. Optic nerve involvement in retinoblastoma. Ophthalmology. 1989;96:217–222
  38. Menon BS, Reddy SC, Wan Maziah WN, et al. Extra ocular retinoblastoma. Med. Pediatr. Oncol. 2000;35:75–76
  39. Messmer EP, Heinrich T, Hopping W, et al. Risk factors for metastases in patients with retinoblastoma. Ophthalmology. 1989;96:217–222
  40. Moll AC, Hoekstra OS, Imhof SM, et al. Flourine-18 flourodeoxyglucose positron emission tomography (PET) to detect vital retinoblastoma in the eye: preliminary experience. Ophthalm. Genet. 2004;25:31–35
  41. Munier FL, Verwey J, Pica A, et al. New developments in external beam radiotherapy in retinoblastoma From lens to normal tissue-sparing techniques. Clin. Exp. Ophthalmol. 2008;36:78–89
  42. Parsam VL, Kannabiran C, Honavar SG, et al. A compréhensive, sensitive and economical approach for the detection of mutations in RB1 gene in retinoblastoma. J. Genet. 2009;88:517–527
  43. Reese, A.B., 1963. Tumors of the eye. Harper and Row, New York, pp. 155–156.
  44. Rootman J, Ellsworth RM, Hofbauer J, et al. Orbital extension of retinoblastoma a clinicopathological study. Can. J. Ophthalmol. 1978;13:72–80
  45. Salim A, Wiknjosastro GH, Danukusumo D, et al. Fetal retinoblastoma. L. Ultrasound Med. 1998;17:717–720
  46. Sanders BM, Draper GJ, Kingston JE. Retinoblastoma in Great Britain 1969–1980: incidence, treatment and survival. Br. J. Ophthalmol. 1988;72:56–583
  47. Schvartzman E, Chantada G, Fandino A, et al. Results of a stage-based approach for the treatment of retinoblastoma. J. Clin. Oncol. 1996;14:1532–1536
  48. Scott IU, Murray TG, Feuer WJ, et al. External beam radiotherapy in retinoblastoma tumor control and comparison of two techniques. Arch. Ophthalmol. 1999;117:766–770
  49. Shields, J.A., Shields, C.L., 1992. Intraocular tumors – A text and Atlas. WB Saunders, Philadelphia, PA, USA.
  50. Shields CL, Shields JA. Retinoblastoma management: Advances in enucleation, intravenous chemoreduction and intra-arterial chemotherapy. Curr. Opin. Ophthalmol. 2010;21:203–212
  51. Shields CL, Shields JA, Baez KA, et al. Optic nerve invasion of retinoblastoma metastatic potential and clinical risk factors. Cancer. 1994;73:692–698
  52. Shields CL, Honavar SG, Shields JA, et al. Vitrectomy in eyes with unsuspected retinoblastoma. Ophthalmology. 2000;107:2250–2255
  53. Singh AD, Shields CL, Shields JA. Prognostic factors in retinoblastoma. J. Pediatr. Ophthalmol. Strabismus. 2000;37:134–141
  54. Stannard C, Lipper S, Sealy R, et al. Retinoblastoma: correlation of invasion of the optic nerve and choroids with prognosis and metastases. Br. J. Ophthalmol. 1979;63:560–570
  55. Uusitalo M, Van Quill K, Scott I, et al. Evaluation of chemoprophylaxis inpatients with unilateral retinoblastoma with high risk features on histopathological examination. Arch. Ophthalmol. 2001;119:41–48
  56. Vemuganti GK, Honavar SG, John R. Clinicopathological profile of retinoblastoma in Asian Indians. Invest. Ophthalmol. Vis. Sci. 2000;41:790;(S)
  57. White L. Chemotherapy in retinoblastoma: current status and future directions. Am. J. Pediatr. Hematol. Oncol. 1991;13:189–201
  58. Wilimas JA, Wilson MW, Haik BG, et al. Development of retinoblastoma programs in Central America. Pediatr. Blood Cancer. 2009;53:42–46
  59. Wolff, J.A., Boesel, C., Ellsworth, R.M. et al., 1978. Childrens Cancer Study Group – Protocol CCSG 962. Childrens Cancer Group, New York.
  60. Young, J., Smith, M.A., Roffers, S.D. et al., 1999. Retinoblastoma. In: Ries, L.A., Smith, M.A., Gurney, J.G. et al. (Eds.), Cancer incidence and survival among children and adolescents United States SEER Program. NIH Pub. No. 99-4649.

PII: S1319-4534(10)00108-6

doi:10.1016/j.sjopt.2010.10.010

Saudi Journal of Ophthalmology
Volume 25, Issue 2 , Pages 159-167, April 2011

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