|Year : 2016 | Volume
| Issue : 3 | Page : 164-170
Retinoblastoma: A comprehensive review
Adarsh S Naik1, S Jyothi2, Parag K Shah1
1 Department of Pediatric Retina and Ocular Oncology, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Coimbatore, Tamil Nadu, India
2 Department of Physiology, Karpagam Faculty of Medical Sciences and Research, Coimbatore, Tamil Nadu, India
|Date of Web Publication||2-May-2017|
Dr. Parag K Shah
Department of Pediatric Retina and Ocular Oncology, Aravind Eye Hospital, Avinashi Road, Coimbatore - 641 014, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Retinoblastoma is the most common intraocular malignancy in childhood. It usually presents before 3 years of age and can be germinal or nongerminal. There has been a paradigm shift in the classification and management of retinoblastoma. This review provide the international retinoblastoma classification, latest classification of vitreous seeds, and current and newer treatment modalities such as intra-arterial and intravitreal chemotherapy.
Keywords: International classification, intra-arterial chemotherapy, intravitreal chemotherapy, retinoblastoma, vitreous seeds
|How to cite this article:|
Naik AS, Jyothi S, Shah PK. Retinoblastoma: A comprehensive review. Kerala J Ophthalmol 2016;28:164-70
| Introduction|| |
Retinoblastoma is the most common intraocular malignancy in children, with a reported incidence ranging from 1 in 15000 to 1 in 18000 live births. There is no racial or gender predisposition in the incidence of retinoblastoma. It is bilateral in approximately 25–35% of the cases. The average age at diagnosis is 18 months, unilateral cases being diagnosed at approximately 24 months and bilateral cases before 12 months. Pawius described retinoblastoma as early as in 1597. In 1809, Wardrop referred to the tumor as fungus hematodes and suggested enucleation as the primary mode of management. The discovery of ophthalmoloscope in 1851 facilitated recognition of specific clinical features of retinoblastoma. Initially thought to be derived from the glial cells, it was called a glioma of the retina by Virchow. Flexner (1891) and Wintersteiner (1897) believed it to be a neuroepithelioma because of the presence of rosettes. Later, there was a consensus that the tumor originated from the retinoblasts, and the American Ophthalmological Society officially accepted the term retinoblastoma in 1926. There has been a paradigm shift in the management of retinoblastoma since then. It is now known as a curable cancer. Among the most important objectives in the management of a child with retinoblastoma is survival followed by preservation of the globe, and focus on visual acuity comes last. Therapy is customized to each individual case and is based on the overall anatomical situation, including threat of metastatic disease, laterality, the number, size and location of the tumor(s), evidence of subretinal fluid, localized or diffuse vitreous seeding, risks for secondary tumors, systemic status, and estimated visual prognosis.
| Genetics of Retinoblastoma|| |
It is caused by a mutation long arm of chromosome 13, band 14 (13q14). RB1 gene is a tumor-suppressor gene, and both the genes have to be mutated to cause this disease. When both the mutations involve only the retinal cells (somatic cells), the child develops a nongerminal type of disease, which is nonheritable. However, when one mutation involves the germinal cell, the child develops the germinal type of disease, which is transmittable to the next generation. Out of the newly diagnosed cases of retinoblastoma, only 6% are familial whereas 94% are sporadic., Bilateral retinoblastomas involve germinal mutations in all cases. Approximately 15% of unilateral sporadic retinoblastoma is caused by germinal mutations affecting only one eye whereas 85% are sporadic.
In 1971, Knudson proposed the two-hit hypothesis. He stated that, for retinoblastoma to develop, two chromosomal mutations are needed. In hereditary retinoblastoma, the initial hit is a germinal mutation, which is inherited and is found in all the cells. The second hit develops in the somatic retinal cells leading to the development of retinoblastoma. Therefore, hereditary cases are predisposed to the development of nonocular tumors such as osteosarcoma. In unilateral sporadic retinoblastoma, both the hits occur during the development of the retina and are somatic mutations. Therefore there is no risk of second nonocular tumors.
Genetic counseling is an important aspect in the management of retinoblastoma. In patients with a positive family history, 40% of the siblings would be at risk of developing retinoblastoma and 40% of the offspring of the affected patient may develop retinoblastoma. In patients with no family history of retinoblastoma, if the affected child has unilateral retinoblastoma, 1% of the siblings are at risk and 8% of the offspring may develop retinoblastoma. In cases of bilateral retinoblastoma with no positive family history, 6% of the siblings and 40% of the offspring have a chance of developing retinoblastoma.
Apart from empiric genetic counseling, as described above, the current trend is to identify the mutation and compute specific antenatal risk. Knowledge of the full range of mutations can aid in the design of screening tests for individuals at risk.
| Histopathology of Retinoblastoma|| |
On low magnification, basophilic areas of tumor are seen along with eosinophilic areas of necrosis and more basophilic areas of calcification within the tumor. Poorly-differentiated tumors consist of small-to-medium sized round cells with large hyperchromatic nuclei and scanty cytoplasm with mitotic figures. Well-differentiated tumors show the presence of rosettes and fleurettes. These can be of various types. Flexner Wintersteiner rosettes consist of columnar cells arranged around a central lumen. This is highly characteristic of retinoblastoma, and is also seen in medulloepithelioma. Homer Wright rosettes consist of cells arranged around a central neuromuscular tangle. This is also found in neuroblastomas, medulloblastomas, and medulloepitheliomas. Pseudorosette refers to the arrangement of tumor cells around blood vessels. They are not signs of good differentiation. Fleurettes are eosinophilic structures composed of tumor cells with pear-shaped eosinophilic processes projecting through a fenestrated membrane. Rosettes and fleurettes indicate that the tumor cells show photoreceptor differentiation. In addition, basophilic deposits (precipitated DNA released after tumor necrosis) can be found in the walls of the lumen of blood vessels.,
| Clinical Manifestations of Retinoblastoma|| |
Leucocoria is the most common presenting feature of retinoblastoma, followed by strabismus, painful blind eye, and loss of vision. [Table 1] lists the common presenting signs and symptoms of retinoblastoma. The clinical presentation of retinoblastoma depends on the stage of the disease. Early lesions are likely to be missed, unless an indirect ophthalmoscopy is performed. The tumor appears as a translucent or white fluffy retinal mass. The child may present with strabismus if the tumor involves the macula or with reduced visual acuity.
There are three types of clinical presentations. Endophytic in which the tumor grows into the vitreous cavity. A yellow white mass progressively fills the entire vitreous cavity and vitreous seeds occur. The retinal vessels are not seen on the tumor surface. Exophytic in which the tumor grows towards the subretinal space. Retinal detachment usually occurs and retinal vessels are seen over the tumor. Diffuse infiltrating tumor in which the tumor diffusely involves the retina causing just a placoid thickness of the retina and not a mass. This is generally seen in older children and usually there is a delay in the diagnosis.
Advanced tumors manifest with proptosis secondary to optic nerve extension or orbital extension and systemic metastasis. Retinoblastoma can spread through the optic nerve with relative ease, especially once the lamina cribrosa is breached. Orbital extension may present with proptosis and is most likely to occur at the site of the scleral emissary veins. Systemic metastasis occurs to the brain, skull, distant bones, and lymph nodes. Some of the atypical manifestations of retinoblastoma include pseudohypopyon, spontaneous hyphema, vitreous hemorrhage, phthisis bulbi, and preseptal or orbital cellulitis.
| Classification|| |
The classification currently used for staging and grouping retinoblastoma is “The International Classification of Retinoblastoma.” It has replaced the older Reese Ellsworth classification, as it could not be applied to current treatment modalities.
This classification consists of two parts:
- Staging for the patient
- Grouping for each eye.
Staging for patient as a whole
There are five stages:
Stage 0: When the child presents with intraocular retinoblastoma with no regional or systemic metastasis, and no enucleation has been performed.
Stage 1: When enucleation has been done in one eye. High-risk pathology features may be present in the enucleated specimen. It may be present in the other eye.
Stage 2: When residual orbital tumor is seen at the cut end of the optic nerve during enucleation.
Stage 3: When there is an overt orbital extension with involvement of preauricular or cervical lymph nodes.
Stage 4: Distant metastasis. It is subdivided into:
- Stage 4a: Non-central nervous system (CNS) spread
- Stage 4b: CNS spread.
Grouping for each eye
This also has five groups:
- Group A: Small tumors which are <3 mm in size and should be located at least 3 mm from the fovea and 1.5 mm from the optic disc
- Group B: Any tumor >3 mm in size (except smaller tumors which are very close to fovea and optic disc as specified in group A). Cuff of exudative retinal detachment <5 mm from the tumor base or <1 quadrant is allowed
- Group C: Any tumor with localized tumor dissemination, i.e., vitreous seeds or subretinal seeds, which are <3 mm from the tumor surface
- Group D: Any tumor with diffuse vitreous or subretinal seeds
- Group E: End-stage disease.
- Neovascular glaucoma
- Tumor or retinal detachment touching the lens
- Anterior segment involvement
- Aseptic orbital cellulitis, etc.
| Diagnosis|| |
A thorough clinical evaluation with careful attention to details, aided by ultrasonography
B scan helps in the diagnosis. Computed tomography is usually avoided to reduce radiation exposure, which can trigger second cancers in children with germinal mutation. Magnetic resonance imaging (MRI) is the preferred modality for diagnosis and to rule out extraocular or intracranial “trilateral” retinoblastoma. A child with suspected retinoblastoma necessarily needs complete ophthalmic evaluation including a dilated fundus examination under anesthesia.
The intraocular pressure is measured and the anterior segment is examined for neovascularization, pseudohypopyon, hyphema, and signs of inflammation. Bilateral fundus examination with 360-degree scleral depression is mandatory. Direct visualization of the tumor by an indirect ophthalmoscope is diagnostic of retinoblastoma in over 90% of the cases. RetCam is a wideangle fundus camera useful in accurately documenting retinoblastoma and monitoring response to therapy. Ultrasonography B scan shows a rounded or irregular intraocular mass with high internal reflectivity representing typical intralesional calcification. On fluorescein angiography, smaller retinoblastoma shows minimally dilated feeding vessels in the arterial phase, blotchy hyperfluorescence in the venous phase, and late staining. Hand-held spectral domain optical coherence Tomography (HH SD-OCT) imaging has dramatically improved the sensitivity to detect early tumors, recurrences, and complications in focal therapy management of retinoblastoma patients. Overall, indirect ophthalmoscopy remains the gold standard for the diagnosis and treatment of active retinoblastoma. Lumbar puncture and bone marrow aspiration for distant staging is done only when there are features of extraocular spread.,
| Management of Retinoblastoma|| |
The primary goal of management of retinoblastoma is to save life. Salvage of the organ (eye) and function (vision) are the secondary and tertiary goals, respectively. The management of retinoblastoma needs a multidisciplinary team approach including an ocular oncologist, pediatric oncologist, radiation oncologist, radiation physicist, genetist and an ophthalmic oncopathologist. The management strategy depends on the stage of the disease – intraocular retinoblastoma, retinoblastoma with high risk characteristics, orbital retinoblastoma, and metastatic retinoblastoma. Management of retinoblastoma is highly individualized and is based on several considerations including age at presentation, laterality, tumor location, tumor staging, visual prognosis, systemic condition, and family and societal perception, and, to a certain extent, the overall prognosis and cost effectiveness of the treatment in a given economic situation.
| Treatment of Intraocular Retinoblastoma|| |
A majority of children with retinoblastoma manifest at the stage when the tumor is confined to the eye. Approximately 90–95% of the children in developed countries present with intraocular retinoblastoma, whereas 60–70% present at this stage in the developing world. Diagnosis of retinoblastoma at this stage and appropriate management are crucial for life, eye, and possible vision salvage.
There are several options for the treatment of retinoblastoma, and the ocular oncologist should be thoroughly familiar with the indications, technique, and expected results of all treatment methods as well as the expected systemic and visual problems.
Various methods to manage intraocular retinoblastoma are focal (cryotherapy, laser photocoagulation, transpupillary thermotherapy, transcleral thermotherapy, plaque brachytherapy), local (external beam radiotherapy, enucleation), and systemic (chemotherapy). While primary focal measures are mainly reserved for small tumors, local and systemic modalities are used to treat advanced retinoblastoma.,
Only focal treatment in the form of cryotherapy, laser photocoagulation, or thermotherapy.
- Cryotherapy involves freezing the tumor till its apex with a cryoprobe and thawing it for 1 min. This is done thrice and is called triple freeze thaw cryotherapy. This treatment is preferred for anterior tumors. The disadvantage is that the scar formed is much bigger than the tumor size 
- Laser photocoagulation involves surrounding the tumor with two to three rows of green laser (532 nm). This cuts off the blood supply and leads to regression of the tumor. This is preferred for posterior tumors. However, here also the scar formed is much bigger than the initial tumor and high power if used on tumor surface can cause iatrogenic vitreous seeding ,
- Transpupillary thermotherapy (TTT) is a method of applying localized heat to tissue that is below the coagulative threshold, and thus sparing the retinal vessels from photocoagulation. The goal is to deliver a temperature of 42–60°C using a diode infrared (810 nm) laser system and induce tumor necrosis. The advantage of TTT is that the scar formed is not bigger than the tumor size.
Here, in addition to local therapy, the tumor needs to be reduced in size with the help of chemotherapy. Here, at least three cycles of chemotherapy (carboplatin, vincristine with or without etoposide) are needed along with local therapy before every cycle. Primary episcleral brachytherapy using either Ru 106 or I 125 seeds is also an option.
Most retinoblastoma centers now adopt a protocol of three-agent chemotherapy using vincristine (0.05 mg/kg), etoposide (5 mg/kg), and carboplatin (18.6 mg/kg) (VEC) delivered 3 weekly over 6 cycles to allow for adequate tumor reduction along with local therapy before each cycle. In addition to this, 2 ml of sub-tenon carboplatin (STC) can be given to tackle the avascular vitreous or subretinal seeds on the day of chemocycles 2, 3, and 4. However, it causes lot of periocular inflammation and might cause a frozen orbit. STC should be avoided along with cryotherapy as this combination can lead to rhegmatogenous retinal detachment. A strikingly fewer numbers of trilateral retinoblastoma were noted in children who were treated with chemotherapy, and hence, Shields concluded that chemotherapy might be protecting against the highly fatal intracranial neuroblastic tumors. This observation is particularly important in children with bilateral or familial retinoblastoma who are at greatest risk for this brain tumor.
In addition to the treatment described above for group C, a reduced dose of 36 Gy of whole-globe EBRT (standard dose is 46 Gy) would be required if reactivation of tumor is seen. EBRT may induce a second cancer among patients with familial disease. Babies who are younger than 12 months of age have a greater risk for second cancers than patients over 12 months of age in the field of irradiation. The 30-year cumulative incidence for second cancers in bilateral retinoblastoma (germinal mutation) has been reported at 35% for patients who received radiation therapy compared with 6% for those who did not receive radiation. This was found to be dependent on patient age at the time of irradiation as well as other factors. Primary enucleation is still an option in unilateral group D cases.
The ideal treatment option for this group is enucleation. The idea is to gently remove the intact eye without seeding the malignancy into the orbit. Orbital implants are routinely placed in children at the time of initial surgery and give excellent cosmetic results with improved prosthesis motility., After enucleation, on histopathology, if high-risk pathology features are present, the child will require six cycles of adjuvant chemotherapy to prevent distant metastasis.
Histopathologic high-risk features are:
- Massive choroidal invasion
- Involvement of tumor past the lamina cribrosa of optic nerve
- Tumor invading into the sclera
- Anterior chamber involvement
- Iris invasion.
In rare cases of bilateral group E, treatment as specified in group D should be attempted. On the basis of the International Classification of Retinoblastoma, treatment success was found in 100% of group A eyes, 93% of group B eyes, and 90% of group C eyes. Group D eyes showed 48% success, however, more recently, these eyes have been managed with additional focal chemotherapy (intra-arterial and intravitreal) to improve control.
| Tumor Regression Patterns|| |
The interpretation of tumor regression can be challenging as retinoblastoma can regress in one of several patterns including type 0 (no remnant visible), type 1 (calcified remnant), type 2 (noncalcified or fish flesh remnant), type 3 (partially calcified with fish flesh remnant), and type 4 (flat scar). These regression patterns are defined post EBRT. However post chemotherapy, types 2 and 3 patterns should be closely watched as they have a high chance of reactivation.
This was first described as early as 1954 by Reese. Later, the Japanese revisited this delivery technique in 1993, followed by the Americans. In this procedure, chemotherapy is given directly in the ophthalmic artery with the help of an interventional radiologist. The benefit is that it allows a high concentration of the drug to the eye (and to the cancer), with far lower concentrations when given systemically. This modality was successful in sparing enucleation in 7 out of 9 children with advanced retinoblastoma, with acceptable ocular toxicity and minimal systemic toxicity, and that many treated eyes could retain or even improve retinal function. In a 3-year experience with this technique on advanced retinoblastoma, only 1 of 28 eyes required enucleation and none required adjuvant systemic chemotherapy or radiation.
The drugs that can be used are melphalan (most common) with or without topotecan hydrochloride or carboplatin. Drug dosage is 5 mg for melphalan, 0.3 mg for topotecan, and 30 mg for carboplatin. The decision to use 1 or 2 drugs is based on clinical judgment with eyes that were more extensively involved (especially widespread seeding) receiving two agents at once. Melphalan is diluted with saline to obtain a volume of 30 ml of solution, which is injected manually by repeated small bolus (pulsatile injection) at a rate of 1 ml/min. After drug delivery, the catheter is removed and hemostasis of the femoral artery is obtained with manual compression. Efficacy and toxicity are judged during the examination under anesthesia performed 3–4 weeks after each treatment. Efficacy is judged on tumor shrinkage and regression, disappearance or calcifications of vitreous and subretinal seeds, and absence of new tumor growth. Toxicity is estimated with electroretinograph study. The mild short-term effects included eyelid edema, blepharoptosis, and orbital congestion, sometimes with temporary dysmotility. The more serious ocular adverse events include arterial occlusion, retinal bleeding, and orbital inflammation in the early phase, and chorioretinal atrophy and ischemic chorioretinopathy in the late phase. Another drawback of this therapy is that, even if enucleation is avoided in some advanced group E eyes, there is a risk of distant metastasis as that child would have received prophylactic chemotherapy if high-risk pathology features were seen on enuleated specimen. There could also be a risk of inducing second cancers in patients with germinal mutation if repeated fluoroscopy was done for this procedure.
Intravitreal administration of chemotherapy for vitreous disease offers the opportunity of delivering the desired tumoricidal drug concentration within the vitreous cavity, however, it is associated with the risk of tumor spread. The use of intravitreal melphalan for vitreous seeding was first introduced in the 1990s by Kaneko and Suzuki, who treated 41 eyes with 8 mg melphalan and simultaneous hyperthermia using a Lagendijk applicator.
Munier et al. described the eligibility criteria for intravitreal chemotherapy injection in retinoblastoma, and described a safety-enhanced technique for intravitreal injection using an antireflux procedure followed by sterilization of the needle track. Eligibility criteria for IViC as assessed by ultrasonic biomicroscopy (UBM) were as follows: (1) absence of invasion of the anterior and posterior chamber; (2) absence of anterior hyaloid detachment; (3) absence of retinal detachment at the entry site; (4) absence of tumor at the entry site; and (5) absence of vitreous seeds at the entry site.
The current literature on retinoblastoma emphasizes vitreous seeding as the primary reason for treatment failure and loss of the eye. In fact, vitreous seeds have been recognized as the defining feature for failure by the Reese and Ellsworth classification group (Vb) and the International Classification of Retinoblastoma group (D). With increased adoption of intravitreal melphalan, salvage rates for eyes with vitreous seeds are surpassing all historical data. Munier also proposed a classification scheme  for the vitreous seeds to aid in the interpretation of disease and enhance reporting in the literature. This classification system is based on morphologic features of seeds and divides vitreous seeds into 3 groups: dust (class 1), spheres (class 2), and clouds (class 3). He also proposed seed regression pattern (type 0 = not visible, type 1 = calcific, type 2 = amorphous, type 3 = types 1 and 2).
Dust results from a displacement of tumor cells into the vitreous appears as small granules of vitreous opacities, and can be seen as a vitreous haze overlying the tumor. They respond to the least amount of time to intravitreal melphalan and required significantly fewer injections (median, 3) before regression is noted. Dust typically regressed into a type 0 pattern, implying that it was not detectable via ophthalmoscopy.
Spheres result from the translocation of tumor cells into the vitreous, which then undergo clonal expansion into spheres. They are spherical opacities within the vitreous, and dust may be present around them. They can be homogeneously opaque and have a translucent outer shell with a relatively transparent or whitish center. The median number of injections required for regression is 5. Following the injections, they initially disperse and eventually disappear on ophthalmoscopy or became calcific (regression type I), or amorphous in shape (regression type II), or even a mixture of these 2 (regression type III).
Clouds result from massive transference of tumor cells into the vitreous and are typically visualized as a dense collection of punctate vitreous opacities. They can appear as a sheet or globule of seed granules and often with wispy edges, and dust and spheres are sometimes also visible. They responded to intravitreal melphalan in a significantly prolonged fashion, with a median of 8 injections. They typically regress to calcific or amorphous granules, and over time, some slowly became undetectable to ophthalmoscopy. Special precaution should be taken while giving intravitreal chemotherpy for retinoblastoma.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bishop JO, Madsen EC. Retinoblastoma. Review of current status. Surv Ophthalmol 1975;19:342-66.
Shields JA, Shields CL. Intraocular tumors – A text and Atlas. 2nd
ed. Lippincott Williams & Wilkins; 2008.
Albert DM. Historic review of retinoblastoma. Ophthalmology 1987;94:654-62.
Jackson E: Report of the committee to investigate and revise the classification of certain retinal conditions. Trans Am Ophthalmol Soc 1926;24:38-9.
Shah PK, Aurora S, Narendran V, Kalpana N. Retinoblastoma Diagnosis, Therapy, and Prognosis. In: Hayat MA, editor. Pediatric Cancer. Volume 3: Chapter 21. pp. 195-200.
Murphree AL, Benedict WF. Retinoblastoma: Clues to human oncogenesis. Science 1984;223:1028-33.
Knudson AG. Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820-3.
Ata-ur-Rasheed M, Vemuganti GK, Honavar SG, Ahmed N, Hasnain SE, Kannabiran C. Mutational analysis of the RB1gene in Indian patients with retinoblastoma. Ophthalmic Genet 2002;23:121-8.
Devarajan B, Prakash L, Kannan TR, Abraham AA, Kim U, Muthukkaruppan V, et al
. Targeted next generation sequencing of RB1 gene for the molecular diagnosis of Retinoblastoma. BMC Cancer 2015;15:320.
Abramson DH, Frank CM, Susman M, Whalen MP, Dunkel IJ, Boyd NW 3rd
. Presenting signs of retinoblastoma. J Pediatr 1998;132:5058.
Shah PK, Narendran V, Kalpana N. Outcomes of Intra- and Extraocular Retinoblastomas from a Single Institute in South India. Ophthalmic Genet 2015;36:248-50.
Chantada G, Doz F, Antoneli CB, Grundy R, Clare Stannard FF, Dunkel IJ, et al
. A proposal for an international retinoblastoma staging system. Pediatr Blood Cancer 2006:47:801-5.
Murphree AL. Intraocular retinoblastoma: The case for a new group classification. Ophthalmol Clin North Am 2005;18:41-53.
Rootman DB, Gonzalez E, Mallipatna A, Vandenhoven C, Hampton L, Dimaras H, et al
. Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: Clinical and morphologic considerations. Br J Ophthalmol 2013;97:59-65.
Moscinski LC, Pendergrass TW, Weiss A, Hvizdala E, Buckley KS, Kalina RE. Recommendations for the use of routine bone marrow aspiration and lumbar punctures in the follow-up of patients with retinoblastoma. J Pediatr Hematol Oncol 1996;18:130-4.
Shields JA, Parsons H, Shields CL, Giblin ME. The role of cryotherapy in the management of retinoblastoma. Am J Ophthalmol 1989;108:260-4.
Shields JA. The expanding role of laser photocoagulation for intraocular tumors. The 1993 H. Christian Zweng Memorial Lecture. Retina 1994;14:310-22
Shields CL, Shields JA, Kiratli H, De Potter PV. Treatment of retinoblastoma with indirect ophthalmoscope laser photocoagulation. J Pediatr Ophthalmol Strabismus 1995;32:317-22.
Shields CL, Santos MC, Diniz W, Gunduz K, Mercado G, Cater JR, et al
. Thermotherapy for retinoblastoma. Arch Ophthalmol 1999;117:885-93.
Tawansy KA, Samuel MA, Shammas M, Murphree AL (2006) Vitreoretinal complications of retinoblastoma treatment. Retina 2006;26(7 Suppl):S47-52.
Shields CL, Meadows AT, Shields JA, Carvalho C, Smith AF. Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol 2001;119:1269-72.
Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: A possible age effect on radiation-related risk. Ophthalmology 1998;105:573-9.
Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with retinoblastoma. Ophthalmology 1988;95:1583-7.
Shields CL, Shields JA, De Potter P, Singh AD. Lack of complications of the hydroxyapatite orbital implant in 250 consecutive cases. Trans Am Ophthalmol Soc 1993;91:177-89.
Christmas NJ, Van Quil IK, Murray TG, Gordon CD, Garonzik S, Tse D, et al
. Evaluation of efficacy and complications: Primary pediatric orbital implants after enucleation. Arch Ophthalmol 2000;118:503-6.
Shields CL, Shields JA, Cater J, Othmane I, Singh AD, Micaily B. Plaque radiotherapy for retinoblastoma: Long-term tumor control and treatment complications in 208 tumors. Ophthalmology 2001;108:2116-21.
Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, et al
. The international classification of retinoblastoma predicts chemoreduction success. Ophthalmology 2006;113:2276-80.
Shields CL, Palamar M, Sharma P, Ramasubramanian A, Leahey A, Meadows AT, et al
. Retinoblastoma regression patterns following chemoreduction and adjuvant therapy in 557 tumors. Arch Ophthalmol 2009;127:282-90.
Reese AB, Hyman GA, Merriam GR Jr, Forrest AW, Kligerman MM. Treatment of retinoblastoma by radiation and triethylenemelamine. AMA Arch Ophthalmol 1954;53:505-13.
Mohri M. The development of a new system of selective ophthalmic arterial infusion for the patients of intraocular retinoblastoma (in Japanese). Keio Igaku 1993;70:679-87.
Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology 2008;115:1398-404.
Brodie SE, Pierre Gobin Y, Dunkel IJ, Kim JW, Abramson DH. Persistence of retinal function after selective ophthalmic artery chemotherapy infusion for retinoblastoma. Doc Ophthalmol 2009;119:13-22.
Abramson DH, Dunkel IJ, Brodie SE, Marr B, Gobin YP. Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology 2010;117:1623-9.
Shields CL, Bianciotto CG, Jabbour P, Griffin GC, Ramasubramanian A, Rosenwasser R, et al
. Intra-arterial chemotherapy for retinoblastoma: Report no. 2, treatment complications. Arch Ophthalmol 2011;129:1407-15.
Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: The long-term prognosis. Ophthalmology 2011;118:2081-7.
Kaneko A, Suzuki S. Eye-preservation treatment of retinoblastoma with vitreous seeding. Jpn J Clin Oncol 2003;33:601-7.
Munier FL, Soliman S, Moulin AP, Gaillard MC, Balmer A, Beck-Popovic M. Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilization of the needle track. Br J Ophthalmol 2012;96:1084-7.
Munier FL, Gaillard MC, Balmer A, Soliman S, Podilsky G, Moulin AP, et al
. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: From prohibition to conditional indications. Br J Ophthalmol 2012;96:1078-83.
Francis JH, Schaiquevich P, Buitrago E, Del Sole MJ, Zapata G, Croxatto JO, et al
. Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: A preclinical and clinical study. Ophthalmology 2014;121:1810-7.
Reese AB, Ellsworth RM. The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol Otolaryngol 1963;67:164-72.
Munier FL. Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24, 2013. Ophthalmic Genet 2014;35:193-207.
Francis JH, Xu XL, Gobin YP, Marr BP, Brodie SE, Abramson DH. Death by water: Precautionary water submersion for intravitreal injection of retinoblastoma eyes. Open Ophthalmol J 2014;8:7-11.