Retinoblastoma

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Retinoblastoma
Classification and external resources
ICD-10 [1]69.2
ICD-9 190.5


Disease Entity[edit | edit source]

Retinoblastoma is an intraocular malignancy with primitive neuroendocrine origins that primarily affects young children.

Incidence[edit | edit source]

Retinoblastoma is the most common intraocular malignancy afflicting children. The estimated incidence varies by country from 3.4 to 42.6 cases per million live births. Within the United States, the incidence is 11.8 cases per million live births among children less than 5 years of age, and retinoblastoma represents 6.1% of all cancers in this age group.[1] Retinoblastoma typically affects young children with the highest incidence in patients less than 4 years old.[2] It occurs equally in males and females. On presentation, approximately 60% of cases are unilateral, and the remaining 40% are bilateral.[3] Patients diagnosed with retinoblastoma are categorized by whether the mutation is germline or somatic. Laterality generally, but imperfectly, predicts whether the retinoblastoma is secondary to a germline or somatic mutation.

Genetics[edit | edit source]

For decades, it has been known that there is a genetic component to this condition. The retinoblastoma susceptibility gene RB1 is a tumor-suppressing gene. It encodes a protein with a regulatory function in the cellular growth cycle at the G1 checkpoint. It is located on subband 13q14.2. Both alleles of the retinoblastoma gene have to be inactivated for tumor development.[2]

Knudson described the "two-hit" mechanism for tumorigenesis in patients with retinoblastoma. Two active copies of the retinoblastoma gene are normally carried in human cells. Both copies must be mutated to lead to the development of retinoblastoma. The initial mutation inactivates one copy of the gene. This mutation may occur in somatic or germline cells. The second mutation occurs in somatic cells. In the majority of cases, this occurs through loss of heterozygosity.

If the first mutation occurs in germline cells, the patient has hereditable retinoblastoma. Germline cases represent approximately 1/3 of retinoblastoma cases.[2] Patients with germline disease tend to have bilateral and multifocal tumors. They also have a significantly increased risk for secondary tumors including primitive neuroendocrine tumors in the brain (so called “trilateral retinoblastoma”). Finally, their offspring will have an increased risk of developing retinoblastoma, as this trait is transmitted in an autosomal dominant fashion with high penetrance (90%).[3] If the RB gene mutation occurs in a somatic cell of the developing retina, it is not heritable.

Most unilateral tumors are sporadic and nonhereditary, but this is not always the case. About 15% of unilateral cases occur in individuals who have germline mutations.[2] In addition, some patients may present initially with unilateral disease but subsequently progress to bilateral involvement. Thus, determining whether the initial mutation is germline is important in the clinical management of these patients, and regular and thorough examinations of both eyes are mandatory. Free testing for retinoblastoma patients to determine the status of the RB1 gene in the germline is available through the eyeGENE program of the National Eye Institute (NEI).

Classification System[edit | edit source]

There are two commonly use classification systems for intraocular retinoblastoma. In the 1950's, the Reese-Ellsworth classification system (see Table 1) was developed to predict the prognosis after treatment with radiation:

Table 1: Reese-Ellsworth classification system
Group 1: Very Favorable
   a. Solitary tumor less than 4 disc diameter (DD) in size, at or behind equator.

   b. Multiple tumors, none over 4 DD in size, all at or behind equator.

Group 2: Favorable
   a. Solitary tumor, 4 to 10 DD in size, at or behind equator.

   b. Multiple tumors, 4 to 10 DD in size, behind equator.

Group 3: Doubtful
   a Any tumor anterior to equator.

   b. Solitary tumor, larger than 10 DD, behind equator.

Group 4: Unfavorable
   a. Multiple tumors, some larger than 10 DD in size.

   b. Any lesion extending anteriorly to the ora serrata.

Group 5: Very Unfavorable
   a. Massive tumor involving over half the retina.

   b. Vitreous seeding.


In the 1990s, the preferred treatment modality shifted from external beam radiation to chemotherapy due to the increased risk of secondary tumors following radiation in patients with retinoblastoma. Clinicians found the Reese-Ellsworth classification system no longer accurately reflected prognosis with the newer treatment modalities. Thus, the International Classification of Retinoblastoma (ICRB) (see Table 2) was developed to better predict those with intraocular retinoblastoma who are likely to be cured without the need for enucleation or external-beam radiation treatment:

Table 2: International Classification of Retinoblastoma (ICRB)
Group A Small intraretinal tumors (< 3mm) away from foveola and disc.
Group B Tumors > 3mm, macular or juxtapapillary location, or with subretinal fluid.
Group C Tumor with focal subretinal or vitreous seeding within 3mm of tumor.
Group D Tumor with diffuse subretinal or vitreous seeding > 3mm from tumor.
Group E Extensive retinoblastoma occupying >50% of the globe with or without neovascular glaucoma, hemorrhage, extension of tumor to optic nerve or anterior chamber.

Pathology[edit | edit source]

Retinoblastoma cells are small and stain blue with hematoxylin and eosin (H&E) stain. Rings of cells surrounding an empty lumen are known as Flexner-Wintersteiner rosettes. They are characteristic but not mandatory to make a diagnosis of retinoblastoma. Homer Wright pseudorosettes, a ring of cells with an eosinophilic fibrillary center, are also commonly found. Fleurettes are retinoblastoma cells that have undergone greater photoreceptor differentiation. Calcification is common in these tumors. Necrosis is also very common and occurs when the tumor outgrows its vascular supply. Necrotic cells appear pink on H&E staining.

Diagnosis[edit | edit source]

Screening[edit | edit source]

The American Academy of Pediatrics policy statement on Red Reflex Examinations in Neonates, Infants, and Children[4] recommends that all neonates, infants, and children should have an examination of the red reflex before discharge from the neonatal nursery and at all subsequent routine health supervision visits. The red reflex test is performed in a dimly lit or dark room with a direct ophthalmoscope or a retinoscope from a distance of about 1-1.5 feet from the patient. Leukocoria (whitening of the red reflex) is the most common presentation of retinoblastoma, and all infants or children with an abnormal red reflex require immediate referral to an ophthalmologist skilled in pediatric examinations.

Newborn screening is of greatest utility in offspring and siblings of patients with retinoblastoma. Offspring and siblings of affected patients require regular screening examinations in childhood. Genetic counseling for families with known retinoblastoma can help to determine whether other family members are at risk for developing disease.

Clinical Presentation[edit | edit source]

Leukocoria in a retinoblastoma patient. (c) 2014 one.aao.org

Early diagnosis of retinoblastoma can maximize the patient's visual prognosis as well as survival rate. Retinoblastoma must always be in the differential diagnosis for any child who presents with strabismus, leukocoria, a red eye, or a cellulitis-like picture. Retinoblastoma is the most important differential diagnosis for a child with leukocoria. Leukocoria, or the loss of the red reflex, is secondary to this tumor filling the globe. Strabismus can also be a presenting sign of retinoblastoma so all patients undergoing a strabismus evaluation should also receive a dilated funduscopic examination.

In rare cases, retinoblastoma can present with pain and inflammation and have a similar presentation to endophthalmitis, uveitis, hemorrhage or preseptal or orbital cellulitis. This more occurs when the tumor has spread outside the globe, portending a poor prognosis. Retinoblastoma can demonstrate local spread along the optic nerve directly into the orbit. It can also metastasize hematogenously to bone, liver, brain and other organs.

History[edit | edit source]

A careful history of present illness, family history, and thorough ophthalmic examination (as well as appropriate ancillary studies) are critical for prompt diagnosis. The clinician must specifically inquire about a family history of blindness, eye tumors, childhood malignancies, or enucleations. A family history of other cancers such as sarcomas may also be suggestive. The parent should be asked if either leukocoria and/or strabismus have been observed. If known, the duration of time from discovery of the leukocoric reflex to presentation in the ophthalmologist's office should be documented. The results of any ancillary testing done prior to the ophthalmologist’s initial consultation with the family should be obtained.

Physical Examination[edit | edit source]

Age-appropriate visual acuity testing should be performed monocularly. External examination should rule out proptosis and signs of orbital cellulitis. Slit lamp examination should look for ciliary injection, pseudohypopyon, or signs of secondary glaucoma. The presence or absence of an afferent pupillary defect should be determined. As mentioned earlier, a dilated fundusopic examination is critical. If there is any suspicion for retinoblastoma, the patient should undergo an examination under anesthesia. An examination under anesthesia with careful scleral depression is necessary to confirm the diagnosis of retinoblastoma as well as to determine the exact location and extent of the tumor(s) and the tumor staging. Photographic documentation for future comparison is recommended. Complete retinal examination of both eyes is necessary to rule out bilateral disease.[5]

Fundus Examination[edit | edit source]

Retinoblastoma classically presents with one or multiple nodular, white or cream colored masses often associated with increased vascularization. There are two primary clinical patterns of retinoblastoma growth.[3] If the tumor grows forward into the vitreous it is known as an endophytic tumor. This form of retinoblastoma often shows vitreous seeding, which causes vitreous haze and opacities. This can eventually progress to involve the anterior chamber and can cause secondary glaucoma and inflammation. When the tumor shows a growth pattern that extends beneath the retina (subretinal) it is described as an exophytic tumor. These tumors can cause exudative retinal detachments and may be associated with significant subretinal seeding.

Diagnostic procedures[edit | edit source]

Additional testing should include A and B-scan ultrasound.[5] Ultrasound will help define tumor height and thickness as well as to confirm associated retinal detachment and calcification.

Computerized tomography (CT) scan can help demonstrate the presence or absence of calcium deposits and help define the size of the tumor. Magnetic resonance imaging (MRI) is often performed to evalute optic nerve involvement, extraocular extension, and also to consider for the possibility of concomitant primitive neuroectodermal tumor (trilateral retinoblastoma). MRI is currently the preferred imaging modality for most clinicians because of radiation associated with CT scans. High doses of radiation can be harmful to all young children but especially to this patient population, who is at increased risk for secondary tumors. Bone marrow examination or lumbar puncture may also be performed in patients where there is concern regarding the extent of disease; particularly with extraocular extension to rule out cerebrospinal fluid (CSF) or bone marrow metastases.

Differential Diagnosis[edit | edit source]

Leukocoria should immediately make the clinician think of retinoblastoma. However, the differential diagnosis includes other entities such as a cataract, Coats’ disease, retinopathy of prematurity, toxocariasis, choroidal coloboma, vitreous hemorrhage, myelinated retinal nerve fibers, and other retinal tumors such as astrocytic hamartoma. Corneal opacities can also produce a white reflex but this can be easily differentiated by clinical inspection. Differentiating retinoblastoma from conditions such as Coats’ disease, persistent fetal vasculature (PFV), or toxocariasis can be a clinical challenge.

Ocular toxocariasis can cause a white, peirpheral retinal mass with a similar appearance to retinoblastoma. Toxocariasis is usually unilateral and associated with more signs of inflammation than retinoblastoma such as injection, pain, photophobia, and anterior chamber and/or vitreous cells. Patients should be questioned about contact with puppies and eating dirt. In addition, a history of fever, eosinophilia, pneumonitis or hepatosplenomegaly would be suggestive of systemic manifestations of peripheral larva migrans. Serum titers positive for toxocara canis would further confirm the diagnosis.

PFV is a congenital condition, and leukocoria becomes noticed clinically early in life. It is typically a unilateral condition, and eyes tend to be microphthalmic. A cataract is often present and may be associated with elongated ciliary processes. If present, these features can help differentiate PFV from retinoblastoma. In Coats’ disease, abnormally dilated, tortuous vessels may be associated with significant exudation causing a mass-like lesion of lipid with associated telangiectatic neovascularization. The exudate in Coats’ disease is more yellow than white because of the presence of cholesterol. Coats’ disease is typically unilateral and predominantly affects boys between 6 to 8 years of age, which is older than the typical patient with retinoblastoma.

A and B-scan ultrasound is helpful to differentiate retinoblastoma from these conditions. They can detect calcification, which would favor a diagnosis of retinoblastoma. It can identify a retrolental mass and a shorter anterior-posterior dimension compared to the unaffected eye, which would favor PFV. Fluorescein angiography would show dilated vessels in retinoblastoma. In contrast, Coats’ disease classically shows focal telangiectasias with profuse leakage into the subretinal space.

Management[edit | edit source]

General treatment[edit | edit source]

Spontaneous regression of retinoblastoma occurs, but is rare. The priorities in the treatment of retinoblastoma are to preserve life, preserve globe, and preserve vision, in that specific order. Minimizing side effects and complications of treatment are also of paramount importance in these very young patients. Enucleation remains the definitive treatment of intraocular retinoblastoma, particularly in the majority of patients who present with unilateral disease. However, the loss of an eye is associated with significant social stigma in certain cultures. In addition, bilateral enucleation is a devastating option for bilaterally affected patients. Treatment modalities that may be successful in globe salvage include systemic chemotherapy with focal consolidation, intra-arterial chemotherapy, and for small tumors, focally destructive therapy (cryopexy, laser photocoagulation, hyperthermia and plaque irradiation).[6] Radiation therapy is avoided if possible, but still has a role to preserve vision in recurrent tumors.

Medical Treatment of Intraocular Retinoblastoma[edit | edit source]

Chemoreduction[edit | edit source]

Prior to the 1990s, external beam radiation (EBRT) played a central role in the treatment of retinoblastoma. Due to disappointingly high recurrence rates, chemotherapy was limited largely to the treatment of metastatic cases. However, with long term follow-up clinicians began realizing how significant an impact EBRT had on the prevalence of secondary tumors, especially in patients with germline mutations. It is estimated that 38.2% of patients with hereditary retinoblastoma will develop a secondary malignancy with an associated long-term mortality rate of 26%.[7][8] The risk of second malignancy is increased more than threefold by EBRT, especially if the patient is less than 1 year of age.[9] The growing reluctance to use EBRT coincided with the rise of more effective chemotherapeutic regimens.

Systemic chemotherapy is administered with focal consolidative therapy. This treatment approach has been coined "chemoreduction" because the goal is to shrink the tumor. Shrinking the tumor increases the success of focal therapies, which are less successful with thicker tumors.[10] Focal therapy is directly destructive to tumor cells and also breaks down the blood ocular barrier and increases penetration of chemotherapeutic agents into the eye.[11] Today, systemic chemotherapy, applied in conjunction with local therapy, is one of the main globe salvaging options in retinoblastoma management.[12]

In patients with advanced bilateral retinoblastoma, traditionally the more severely affected eye has been enucleated, while the less severely affected eye has undergone chemoreduction with or without external beam irradiation. In cases where only one eye harbors tumor, enucleation is usually considered when the tumor is large and there is poor vision potential. As chemoreduction has proven its efficacy, clinicians are expanding its clinical indications to allow more eyes to be saved.

The Children’s Oncology Group (COG) currently has multiple trials evaluating chemotherapy regimens in conjunction with focal consolidation. Since group A eyes are often easily managed with focal therapies alone, no COG trial exists for this group. For group B tumors, a two agent protocol involving vincristine and low-dose carboplatin along with local therapy was being evaluated (COG ARET0331) but has now reached a stopping point. Group C and D tumors were being treated with three agent chemotherapy involving vincristine, high-dose carboplatin, and etoposide along with local therapy as well as subtenon injection of carboplatin (COG ARET0231). These trials have also reached stopping points. Enucleation is recommended for group E eyes. Children with tumor massively involving the optic nerve, orbit, brain or present at distant sites are currently being enrolled in a COG group F trial.

Intra-arterial Chemotherapy[edit | edit source]

In the future, more localized delivery of medication may help decrease the systemic side effects of chemotherapeutic agents while still allowing the success clinicians have seen with chemoreduction techniques. The quest for local delivery for chemotherapeutics is not new. From intravitreal injection, subconjunctival injection, to more complex delivery systems incorporating fibrin sealant, clinicians have been evaluating the possibility for local delivery of antineoplastics around the eye for decades. In addition to improving intravitreal penetration, these approaches would minimize systemic toxicity and possibly be more available in the developing world where retinoblastoma remains a lethal disease.

Recently, significant attention has been focused on intra-arterial delivery of chemotherapeutic agents. Based on early attempts in Japan to directly cannulate the carotid artery in order to deliver antineoplastic drugs to the eye, Abramson and colleagues recently modified the Japanese protocol to cannulate the ophthalmic artery.[13] This technique has been called supra-selective intra-arterial chemotherapy. Using Melphalan, Abramson and colleagues have reported good response rates. However, side effects have also been described including sectoral occlusive choroidopathy, and concerns exist about the potential to cause strokes with this method of delivery.[14] The total dose of whole body radiation given with multiple fluoroscopies also remains undefined. A randomized clinical trial has been recommended to determine the efficacy and safety of this approach, as well as to determine the optimum chemotherapeutic agent. Such a trial is currently under consideration by the COG cooperative group of the NCI.

Surgical Treatment of Intraocular Retinoblastoma[edit | edit source]

Eyes with large tumor burden (Group E eyes) and eyes that progress despite conservative treatments require enucleation. When an eye is enucleated for retinoblastoma, the goal is to remove as much optic nerve as possible to try ensure that the cut end of the nerve is free from tumor. The globe is sent for pathologic evaluation.  Pathologic evaluation has clinical importance because it determines whether there are any pathologic risk factors for extraocular spread. Pathologic risk factors (PRF) that have been identified include: 1. choroidal invasion, 2. post-laminar invasion of the optic nerve, 3. scleral invasion, and 4. involvement of the anterior chamber. If PRFs are present, consideration should be given for adjuvant chemotherapy to decrease the risk of extraocular relapse.[15] At the time of enucleation, the largest orbital implant is placed in order to encourage normal development of the pediatric orbit. Patients who have an eye enucleated will continue to be followed to ensure there is no evidence of tumor in the other eye. They will also need fitting for an ocular prosthesis.

Medical Treatment of Extraocular Retinoblastoma[edit | edit source]

Historically, extraocular retinoblastoma was nearly universally fatal.  If the retinoblastoma remained confined to the orbit, there was only  a 10% survival rate, and cases of survival with metastatic retinoblastoma was anecdotal.[16] However, as chemotherapeutic regimens have improved, the prognosis has also improved.

For extraocular retinoblastoma limited to the orbit, clinicians are finding success with neoadjuvant chemotherapy to shrink the tumor.  This is followed by surgical debulking and post-operative chemotherapy and radiation if necessary.[17][18] For systemic metastases, especially cases with CNS involvement, aggressive treatment with high dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) is recommended.  HDC involves the administration of high doses of chemotherapeutic agents with the aim to overcome tumor resistance and completely eradicate neoplastic cells.  Unfortunately, these lethal doses are also myeloablative and concurrent ASCR must be performed to allow future reconstitution of the bone marrow. Though toxic, case series of survival after this treatment regimen are being reported.[19][20]

Currently there is a Children’s Oncology Group (COG) trial evaluating high dose systemic chemotherapy using four cycles of induction chemotherapy with vincristine, cisplatin, cyclophosphamide and etoposide followed by one cycle of high-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for malignant brain and spinal tumors. Though promising, treatment efforts remain focused on early detection and treatment to prevent extraocular disease in the first place.

Trilateral Retinoblastoma[edit | edit source]

In additional to CNS metastases, patients with retinoblastoma can develop intracranial involvement by developing a concurrent CNS primitive neuroectodermal tumor (PNET). Trilateral retinoblastoma is the term often applied to a PNET in the setting of bilateral retinoblastoma. It is a rare neoplasm that occurs in patients with germline mutations. While this is more common in bilateral cases, some patients with unilateral retinoblastoma that carry germline mutations are also at risk for developing this tumor.[21] Thus the term trilateral retinoblastoma can create a false sense of security with unilaterally affected germline patients.

The treatment regimen for patients with PNET is similar to patients with CNS metastases. The prognosis is also dismal. As such, early detection and treatment of PNETs is recommended.  Recently it was noted that there was a decrease in the incidence of PNETs as clinicians came to rely more on chemotherapy over EBRT. This is hypothesized to be secondary to either a prophylactic effect due to systemic chemotherapy or because fewer patients are receiving radiation.[22][23] Regardless, systemic chemotherapy should be strongly considered for germline cases of retinoblastoma over local (i.e. intra-arterial, etc.) delivery.

Follow up[edit | edit source]

Patients who undergo any form of eye sparing treatment (external beam radiation, chemoreduction) need frequent follow-up examinations. Tumor regression is followed closely, documenting the appearance, size, location and number of tumors during each examination. When tumor regresses after treatment, it can appear as a white, calcific mass or appear translucent and resemble fish flesh. A typical schedule would require examinations under general anesthesia every 6-8 weeks until age three, followed by less frequent examinations if the disease becomes quiescent.5 Patients with hereditary retinoblastoma are at increased lifetime risk of developing secondary malignancies throughout the body. The most common secondary tumor is osteosarcoma.[24] Other tumors include PNETs, fibrosarcoma, and melanoma. Patients who have been treated with radiation are at higher risk for secondary tumors in the field of treatment. Long term follow-up of all retinoblastoma patients is mandatory with special vigilance if patients have germline mutations.

Additional Resources[edit | edit source]


References[edit | edit source]

  1. Broaddus, E., Topham, A., and Singh, A.D. 2009. Incidence of retinoblastoma in the USA: 1975-2004. Br J Ophthalmol. 93: 21-3.
  2. 2.0 2.1 2.2 2.3 Abramson DH, Schefler AC. Update on retinoblastoma. Retina. 2004 Dec;24:828-48.
  3. 3.0 3.1 3.2 Shields JA, Shields CL. Ocular tumors. A text and atlas. Philadelphia, PA: Saunders; 1992. p.311-12.
  4. American Academy of Pediatrics policy statement- Red Reflex Examination in Neonates, Infants, and Children. Pediatrics 2008;122: 1401-1404.
  5. 5.0 5.1 Lin P, O’Brien JM. Frontiers in the Management of Retinoblastoma. Am J Ophthalmol 2009; 148: 142-8.
  6. Hamel P, Budning AS, Heon E, et al. Focal Therapy in the Management of Retinoblastoma: When to Start and When to Stop. J AAPOS 2000;4:334-337.
  7. Eng C, Li FP, Abramson DH, et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst. 1993;85:1121-8.
  8. Kleinerman RA, Tucker MA, Tarone RE, et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005;23:2272-9.
  9. 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.
  10. Shields JA, Shields CL, De Potter P. Photocoagulation of retinoblastoma. Int Ophthalmol Clin. 1993;33:95-9.
  11. Abramson DH, Frank CM, Chantada GL, de Totah AB, de Pifano IT, Ramírez GT, Gomez RT, Fandino AT, Tran HT, Madden TJ, Dunkel IJ. Intraocular carboplatin concentrations following intravenous administration for human intraocular retinoblastoma. Ophthalmic Genet. 1999 Mar;20:31-6.
  12. Shields CL, De Potter P, Himelstein BP, et al. Chemoreduction in the initial reduction of intraocular retinoblastoma. Arch Ophthalmol 1996;114:1330-8.
  13. 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 Aug;115: 1398-404.
  14. Shields CL, Bianciotto CG, Jabbour P, Griffin GC, Ramasubramanian A, Rosenwasser R, Shields JA. Intra-arterial chemotherapy for retinoblastoma: Report No 2. Treatment Complications. Arch Ophthalmol. 2011 Nov; 129: 1407-15.
  15. International Retinoblastoma Staging Working Group. World disparities in risk definition and management of retinoblastoma: a report from the International Retinoblastoma Staging Working Group. Pediatr Blood Cancer. 2008;50:692-4.
  16. Rootman J, Ellsworth RM, Hofbauer J, Kitchen D. Orbital extension of retinoblastoma: a clinicopathological study. Can J Ophthalmol. 1978;13:72-80.
  17. Chantada G, Fandiño A, Casak S, Manzitti J, Raslawski E, Schvartzman E. Treatment of overt extraocular retinoblastoma. Med Pediatr Oncol. 2003;40:158-61.
  18. Kiratli H, Bilgiç S, Ozerdem U. Management of massive orbital involvement of intraocular retinoblastoma. Ophthalmology. 1998;105:322-6.
  19. Kremens B, Wieland R, Reinhard H, et al. High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Bone Marrow Transplant. 2003;31:281-4.
  20. Leal-Leal CA, Rivera-Luna R, Flores-Rojo M, Juárez-Echenique JC, Ordaz JC, Amador-Zarco J. Survival in extra-orbital metastatic retinoblastoma:treatment results. Clin Transl Oncol. 2006;8:39-44.
  21. Ibarra MS and O'Brien JM. Is Screening for Primitive Neuroectodermal Tumors in Patients With Unilateral Retinoblastoma Necessary? J AAPOS 2000;4:54-6.
  22. 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.
  23. Moll AC, Imhof SM, Schouten-van Meeteren AY, et al. Chemoreduction for retinoblastoma. Arch Ophthalmol. 2003;121:1513.
  24. MacCarthy A, Bayne AM, Draper GJ, Eatock EM, Kroll ME, Stiller CA, Vincent TJ, Hawkins MM, Jenkinson HC, Kingston JE, Neale R, Murphy MF. Non-ocular tumours followein retinoblastoma in Great Britain 1951 to 2004. BR J Ophthalmol. 2009 Sep;93: 1159-62.