Early Human Development 86 (2010) 619–625

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Early Human Development
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev

Retinoblastoma — Current treatment and future direction
Manoj V. Parulekar ⁎
Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, United Kingdom

a r t i c l e
Keywords: Retinoblastoma Infant Tumour Ocular Mutation Heritable Chemotherapy Screening Intra-arterial Enucleation Cancer

i n f o

a b s t r a c t
Retinoblastoma is the commonest primary ocular malignancy of childhood. There are two forms — heritable and non heritable. Heritable retinoblastoma is a cancer susceptibility syndrome. Presentation is in the first few years of life, sometimes in the neonatal period. Early detection and prompt treatment can give cure rates up to 95% for intraocular tumours, but extraocular disease carries a very high mortality. The diagnosis is essentially clinical and biopsy is contraindicated due to the risk of extraocular spread. Treatment requires significant multidisciplinary input, with local ophthalmic treatment, systemic chemotherapy and external beam or plaque radiotherapy, or surgery to remove the affected eye. Screening of family members is essential for early detection. Lifelong surveillance of mutation carriers is needed due to the risk of second cancers. Newer treatment modalities including intra-arterial chemotherapy have been added to the therapeutic armamentarium in recent years. © 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Retinoblastoma is a malignant tumour arising from the developing retina. It typically presents in the first 2–3 years of life, often during infancy. The tumour is confined to the eye in the early stages, and cure rates for intraocular retinoblastoma can be as high as 95%. Extraocular spread (Fig. 1) carries a very poor prognosis [1], with cure rates below 5–10%. Early diagnosis and prompt treatment is therefore crucial to save life and vision.

3. Genetics Understanding the genetics of retinoblastoma is important when planning management. The tumour arises from primitive cells of the developing retina with loss of function of the Rb tumour suppressor gene (Ch13q14). [6] The retinoblastoma gene was the first oncogene to be cloned, and is the prototype genetic cancer syndrome [7]. Other genetic cancer syndromes include the Li–Fraumeni syndrome and Xeroderma pigmentosum. There are two copies (alleles) of the Rb gene in every cell in the body, and at least one functioning allele is required to prevent the development of retinoblastoma in a retinal cell. Loss of both alleles will result in retinoblastoma tumours. Interestingly, in 1973 Knudson, a statistician proposed that two separate mutational events — M1 and M2 that result in loss or inactivation of both Rb gene copies are required to initiate the tumour on the basis of his epidemiological studies, and this came to be known as the Knudson ‘two-hit’ hypothesis which has stood the test of time [8]. Recent evidence suggests that tumour initiation (retinoma) can occur with 2 hits, but subsequent mutations (M3–Mn) are necessary for the tumour to grow into retinoblastoma [9]. Loss of segments of the chromosome carrying the Rb1 genetic material e.g. chromosome 13q14 deletion can also result in retinoblastoma, and are often associated with developmental delay and dysmorphic features. The two hits can occur in one of two situations. In the genetic (also referred to as germline or heritable) form, every cell in the body is missing one copy of the Rb gene, the mutation occurring at the zygote stage. Every retinal cell is missing one copy of the gene, and can potentially give rise to a tumour. The other situation is the somatic

2. Epidemiology Retinoblastoma is the commonest primary malignant intraocular tumour of childhood accounting for up to 1% of all tumours in infancy. The age adjusted annual incidence is 12 per million population [2] under the age of 4 years. The incidence of sporadic retinoblastoma is 1 in 15,000–20,000 live births, with no gender or racial predilection. As expected, the burden of disease is highest in populous developing countries in proportion to the birth rate [3]. The median age at presentation is under 12 months in heritable cases, and closer to 24 months in sporadic cases [4]. Presentation after the age of 6 years is extremely rare, although there are isolated reports of cases presenting as late as 26 years [5].

⁎ Tel.: +44 121 333 9465; fax: +44 121 333 9461. E-mail addresses: manojparulekar@aol.com, manoj.parulekar@bch.nhs.uk. 0378-3782/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2010.08.022

Of the unilateral cases. Less common modes of presentation are reduced vision detected at school screening. Inheritance patterns Retinoblastoma may be inherited or occur sporadically. 40% of all cases are bilateral (and necessarily germline). This constitutes the first hit. This is more common with unilateral cases. and nystagmus or searching eye movements as a result of the tumour involving the central part of the retina (macula) in both eyes (Fig. and gives rise to a tumour. Unilateral cases (most of which are somatic mutations) usually present later. Less common presenting features include phthisis bulbi (shrinkage of the globe). and carry the same risks as bilateral germline cases. 4. Fig. pseudohypopyon (cells in the anterior chamber appearing as a layered white material) rubeosis (dilatation of iris vessels) and hyphaema (bleeding into the anterior chamber).15]. orbital inflammation and excess watering. White reflex on digital photography — leucocoria. 1. However. enlargement of the globe or change in iris color (heterochromia). 5. the Honduran retinoblastoma campaign was associated with a reduction in the proportion presenting with advanced disease [13]. Germline mutations are highly penetrant. and lead to earlier detection. often at the age of 2 to 3 years or older. 15% are germline. often in infancy. 6. Careful screening of the fellow eye is essential in all such cases through childhood. Bilateral cases often present with poor vision. Presentation Unilateral and bilateral cases differ in the manner and timing of presentation. and this continues to be the subject of campaigns to raise awareness. acute red eye. Anterior segment involvement may result in raised pressure in the eye (glaucoma). There is however insufficient evidence in the literature to support or refute this theory [10. It has been suggested that there is an increased incidence of retinoblastoma in babies born of assisted conception. and 60% are unilateral (which could be somatic or germline). it is more likely to be germline (heritable) as described earlier. (non heritable) type where a single developing retinal cell loses one copy of the Rb gene during retinal development — the rest of the body cells are normal. . Squint. the tumour can spread along the optic nerve to involve the central nervous system. The commonest presenting features in unilateral cases are leukocoria (60%) and squint (20%). 1). The typical findings are one or more round white retinal mass(es) growing into the vitreous cavity (endophytic) or growing into the sub retinal space (exophytic). Digital flash photography can highlight the white reflex (Fig. 3. A third of the sporadic cases arise from new germline mutations which are heritable (can be passed to offspring but not inherited from the parent). and such cases can present early. This makes it easier to understand why genetic cases often have multiple tumours in one or both eyes (bilateral or unilateral multifocal). 2). Late presentation with proptosis (forward displacement of the eye) or fungating orbital mass is not unusual in countries with limited access to healthcare and carries a very poor prognosis (Fig. 2). Diagnostic biopsy is contraindicated because of the risk of extraocular spread [14. However. refractive errors and photographs taken from an angle (off axis) can similarly produce a white reflex diminishing the specificity of this technique as a screening test [12]. Diagnosis The diagnosis of retinoblastoma is essentially clinical. The second hit is a random event. Over 90% of cases are sporadic (with no family history). approximately 15% of unilateral cases carry the germline mutation.11]. A characteristic feature highly supportive of the diagnosis is visible calcification within the tumour on ophthalmoscopy. Some cases may present with periocular inflammation.V.620 M. (Fig. Multiple tumours in both eyes in a 4 month old with germline retinoblastoma. If a child presents with unilateral retinoblastoma early in life. Early presentation within the first few months of life is usual for bilateral cases. and even at birth in some cases. while somatic cases are always unilateral and unifocal. Advanced cases are rarely seen in economically advanced countries. Over 90% of children carrying the Rb gene defect will develop retinoblastoma. Parulekar / Early Human Development 86 (2010) 619–625 Fig. This might also be detectable on ultrasonography [16]. 2. 3) in some cases. 3). Only a minority of cases with a white reflex on photographs will turn out to have retinoblastoma however. In advanced cases. and may be supported by imaging in some cases. or through the choroid resulting in haematogenous spread to bones. In most of these cases the mutation is somatic and gives rise to isolated unilateral disease. lungs and abdominal solid organs. Advanced retinoblastoma with fungating orbital mass. Fragments of the tumour can spread as vitreous or sub retinal seeds (Fig. or leukocoria (white reflex in the pupil) noticed by the parents in one or both eyes Fig. with a high risk of developing more tumours in the same or fellow eye.

Enucleation: is the oldest treatment. Congenital cataracts — present with a white pupil (leukocoria) 2. Typically. Characteristic histological features include abnormal patterns of retinoblasts such as the Flexner–Wintersteiner rosettes. Imaging B scan ultrasonography: confirms the presence of masses in the posterior segment of the eye. . 8. or non porous such as silicone or acrylic. and vincristine (referred to as JOE or CEV chemotherapy). and nephrotoxicity [24.23]. Congenital glaucoma presenting with a cloudy. It is also very effective against vitreous and sub-retinal diseases. 7. This includes i. 5. and fleurettes. Patau's syndrome. or recurrent disease not responsive to all other forms of treatment. This treatment is suitable for larger.1. if the child presents with signs of raised intracranial pressure (to look for pinealblastoma–trilateral retinoblastoma) or if the diagnosis is in doubt [18]. Edward's syndrome. teletherapy) or using a radioactive plaque (brachytherapy). Walker Warburg and other neuronal migration disorders 4. Differential diagnosis These can easily be distinguished from retinoblastoma by ophthalmologists with experience in retinoblastoma management [17]. The eye is removed with a long segment of optic nerve and sent for histology.M. Genetic testing Mutation testing: is an essential investigation. its main role is to shrink the tumours to a size where laser treatment can be effective (chemoreduction). or localized vitreous disease close to the retina. A prosthetic shell painted to match the other eye is fitted in due course for cosmesis. Treatment Retinoblastoma has evolved from a deadly childhood cancer to a largely curable cancer within the past 40 years. Lesions simulating retinoblastoma — 4 week old boy with Coat's disease. Laser is delivered through dilated pupils using the indirect ophthalmoscope or microscope. 4. Congenital infections like Toxocara affecting the eye 6. including hearing loss with carboplatin. future siblings and offspring. 9. Cryotherapy: using a special probe applied through the sclera to produce temperatures as low as −60 to −80 °C results in cryonecrosis of tumours. There are significant short and long term side effects of chemotherapy. peripheral tumours. Investigations 7. Persistent fetal vasculature PFV (previously called persistent hyperplastic primary vitreous PHPV) results from failure of regression of fetal vessels in the vitreous 3. which has major implications for determining the risk to unaffected relatives. etoposide. red and watery eye Fig. The implant material may be porous such as porous polyethylene (Medpor) or hydroxyapatite. Chemotherapy: a very valuable addition to our armamentarium over the past 2 decades. or larger tumours after they have been shrunk to a treatable size with chemotherapy (chemoreduction). and can be performed on peripheral blood. imaging is not routinely indicated.2. or bioceramic. In contrast. X-ray and CT scan are best avoided as any dose of radiation magnifies the risk of secondary malignancies in germline cases. External beam radiotherapy has significant risks including induced secondary malignancies (major risk in germline cases) within the radiation field. this involves 4–6 cycles at 3 weekly intervals. Characteristic findings are intra-lesional calcification with high internal reflectivity and acoustic shadowing. dry eyes and soft tissue and bony atrophy. The two common laser wavelengths are 532 nM green light and 810 nM infrared light. MRI may be useful if there is suspicion of extraocular (particularly intracranial) spread. EBRT is now reserved for diffuse disease in the only remaining eye. and invaluable for extraocular involvement and metastases. and tumour DNA studies to identify the mutations. cataracts.a vascular retinopathy resulting in exudation of lipid under the retina (Fig. and is curative for intraocular retinoblastoma. Retinal dysplasia seen in Norrie's disease. 4). This often helps distinguish between germline and somatic cases. This requires significant multidisciplinary input and should be coordinated by a specialised centre. plaque brachytherapy involves attaching a radioactive plaque of Iodine 131I or Ruthenium 106Ru onto the sclera for a specified period (hours to days) to deliver a high dose of radiation to a localized area without the risks of EBRT. Once the mainstay of treatment. It is the treatment of choice for advanced uniocular disease or the worse eye of bilateral cases [26]. Laser treatment is however not effective for vitreous seeds. Parulekar / Early Human Development 86 (2010) 619–625 621 The diagnosis can be confirmed histologically if the eye is removed surgically (enucleation — see below). Newer treatment modalities: over the past few years. Staging The new international classification of intraocular retinoblastoma has 5 groups — A to E of increasing severity. It is usual to replace the lost volume of the enucleated globe with a spherical implant of appropriate size depending on the age of the child. and tumour tissue if available (from the enucleated eye). Radiotherapy: this could be in the form of external beam radiotherapy (EBRT. It is highly effective against localized vitreous disease and for elevated tumours where laser is ineffective [22. 7. Homer Wright rosettes.V.25]. The various modalities of treatment are: Laser treatment: laser treatment is suitable for primary treatment of smaller tumours. 1. Large spot 810 nM treatment heats the tumour slowly (thermotherapy) to produce necrosis and is preferred by many centres [21]. 8. These mutations are then tested against peripheral blood to establish if it is a germline or somatic case. Early onset Coat's disease. There is also a staging system for extraocular disease [20]. Periocular injections of carboplatin and other agents to increase the intraocular levels of the drug and enhance efficacy. CT/MRI scan: apart from ultrasonography.1. Common regimens include carboplatin. research has focused on developing techniques for local delivery of chemotherapy to minimize systemic adverse effects. Current treatment strategies aim to salvage the eye and provide the best visual outcome possible. [19].

g. maternal blood is tested using DNA amplification. lack of a satisfactory animal model. Prosthesis fitting for enucleated eyes — is an important part of rehabilitation. there is no risk of second cancers. It is likely future research will be directed towards targeted molecular therapy to individualize treatment. and the patients when they reach adolescence about the inheritance of retinoblastoma. vision and a chronic illness 3. Although the sensitivity of this technique is quite low. Local treatment may be continued at further EUAs until all tumours are inactive [29. v. The most significant advance in recent years has been the interventional radiological technique of intra-arterial chemotherapy (IAC). and particularly if the child is shown to carry the mutation on CVS or amniocentesis. the initial results are encouraging in selected cases [27]. A suggested protocol is shown in Table 2. 5. testing can be offered to relatives to determine if they are at risk of suffering/passing on the disease. Supportive treatment 1. In cases where the mother is healthy and the father is the mutation carrier. 10.V. Free fetal DNA testing. one can deduce that it has come from the fetus which must be carrying the mutation. 14. avoiding systemic side effects. Chorion villous sampling (CVS) or amniocentesis are interventional techniques to obtain fetal tissue samples prenatally and test for the RB mutation [32]. Long term oncological surveillance especially for germline cases — this is best undertaken by oncologists. saving eyes and lives. Additionally. If the mutation is found in maternal blood. and treatment may have to be delayed until term. Protective eye wear for the better/remaining eye during contact sport 4. Parulekar / Early Human Development 86 (2010) 619–625 ii. The widely accepted new international classification system. 6. and risk to siblings and offspring.30]. iii. As a result. The diagnosis is clinical. chemotherapy with laser. 3. Developing better animal models 5. Screening for retinoblastoma Screening close relatives of retinoblastoma patients is invaluable in early detection and treatment. and has a 95% cure rate with appropriate treatment. If the mutation for the index case is known. Most centres will have protocols for screening. cryotherapy or plaque brachytherapy helps minimize adverse effects [28]. in experienced hands. chemotherapy is given over 4–6 cycles at 3 weekly intervals. The obvious disadvantage of this technique is the need for in-vitro fertilization (IVF) to produce and then select embryos [31]. there are several options to prevent retinoblastoma or enable early detection i. iii. 12. Screening is offered if – mutation positive or – if the mutation is not known for the index case. This involves transfemoral artery canulation to allow delivery of a high dose of the chemotherapeutic agent Melphalan into the ophthalmic artery. Improvements in local drug delivery methods will address the problem of systemic toxicity from existing chemotherapy regimens. iv. There are also increased risks of surgical intervention such as caesarean section and forceps in induced births. and multicentre studies currently underway will pave the way for a more evidence based approach to retinoblastoma management. A better understanding of genotype–phenotype relationships in retinoblastoma that will be useful in the multidisciplinary management of this disease. Direct injection of drugs into the vitreous cavity has been attempted by some centres. Prenatal diagnosis — the role of imaging and tissue sampling If there is a family history of retinoblastoma and the mutation in the affected parent is known. A combination of treatment modalities e. Prenatal ultrasound — in cases with a family history. anti angiogenic agents. Cord blood testing.g. The risk of secondary malignancies. This can then be confirmed at birth with cord blood testing. it may be possible to detect large tumours developing in the last few weeks of pregnancy. with EUAs before each cycle to monitor response and apply local treatment (laser or cryotherapy). Exploring biologic treatment e. Screening is not needed if the relative does not carry . A typical care pathway is shown in Table 1. During active treatment. growth factors etc. ii.622 M. However. Close monitoring with examinations under anaesthesia (EUA) at decreasing frequency as the child grows older is important for early detection of recurrent or new tumours. The obstetric team can collect cord blood and send it to a reference laboratory to test for the Rb mutation. 2. Minimising the side effects of treatment 4. Cataract surgery if needed should be delayed for at least 1–2 years after active treatment 13. there is no consensus on this subject. Some centres advocate induction of labour at 36 weeks to enable treatment in such cases. B scan ultrasonography may be advisable in the later stages of pregnancy to look for development of tumours. this technique has not been adopted widely due to the fear of producing extraocular spread of the tumour. Current research is directed towards 1. Treatment principles Retinoblastoma is a unique cancer by virtue of its confinement within the scleral envelope. usually a few weeks after surgery. Unaffected embryos are selectively implanted ensuring the fetus is born free of the retinoblastoma mutation and does not require screening. with examinations without anaesthesia for older children. There can however be some difficulty giving chemotherapy to preterm babies. Research directions The relatively small numbers of cases seen by each centre. and gene therapy to prevent tumour formation. 11. This exciting new technique involves testing free (extracellular) fetal DNA which is known to cross the placental barrier. One cell is removed from the embryo to look for the mutation. advice about risk factors like smoking and how to look out for early warning signs should be discussed with adolescent patients. Counseling — parents should be counseled soon after diagnosis. and numerous non-comparable staging systems have hindered retinoblastoma research in the past. Psychological support for children and families — to deal with loss of eye. and risk cannot be excluded. and it is important to avoid breaching this envelope with an intraocular procedure such as diagnostic biopsy to avoid the mortality associated with extraocular spread. Pre-implantation genetic diagnosis (PIGD) involves screening embryos at the blastocyst stage. Although long term experience with this technique is lacking. 2. and no risk to future generations.

EUA. B Scan. Retcam. 623 Leucocoria / strabismus Paediatrician / family physician Ophthalmologist Optometrist / orthoptic screening Clinic exam / EUA B Scan.M.V. Parulekar / Early Human Development 86 (2010) 619–625 Table 1 Care pathway for management of retinoblastoma. Retcam Retinoblastoma service Oncologist Ophthalmologist Geneticist Clinical examination Blood tests VA. NO CT SCAN MRI only if suspicion of extra-ocular extension or hydrocephalus Family history blood for mutation studies from proband Multi-disciplinary team meeting Multi-disciplinary team meeting Unilateral Bilateral E/E A-D E Chemotherapy + laser/cryo Primary enucleation Failure Plaque or intraarterial chemotherapy Failure E/A-D Chemotherapy and/or laser/cryotherapy Chemotherapy + laser/cryo Failure Plaque or intraarterial chemotherapy Failure Failure Plaque or intra-arterial chemotherapy or secondary enucleation External beam radiotherapy or secondary enucleation .

• Prenatal diagnosis is available. Rebelo MS. Ophthalmology 1997 Jan. Juárez-Echenique JC. Survival in extra-orbital metastatic retinoblastoma:treatment results. Sharma T. Developing a global network of retinoblastoma treatment centres that share information and offer advice. Prognosis for life Most untreated tumours proceed to local invasion and metastasis to cause death within 2 years. optic nerve involvement.126(3):715–20. the tumour may spontaneously stop growing to form a retinoma. [2] de Camargo B. • CT scan is best avoided due to the risk of inducing second cancers. The management of these cases can be challenging [33]. Am J Med Genet 2002 Jul 22. or necrose to cause phthisis bulbi (shrunken globe). Early detection to minimize visual morbidity remains the focus of research in countries with universal access to healthcare. Flores-Rojo M. Kane JR. Fu L. cryotherapy and plaque brachytherapy. extraocular spread and older age at presentation. Wilson MW. 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Recurrence Recurrence can develop within the eye in previously treated tumours.8(1):39–44. Antoneli C. Genetic retinoblastoma often presents in infancy while somatic retinoblastoma usually presents later. Qaddoumi I. Noronha CP. Acknowledgements My patients and their families who deal with the disease with such dignity and bravery. Risk of second cancers and the role of long term surveillance Patients with germline mutations are at increased risk of developing secondary malignancies such as pinealblastoma (trilateral retinoblastoma) [34] ectopic intracranial retinoblastoma. • There are 2 forms. advocating a healthy lifestyle and to promptly seek medical advice. Font RL. • Diagnostic biopsy is strictly contra-indicated due to risk of extraocular spread. Retinoblastoma in the first year of life.47(5):1736–45. Prognosis for vision The prognosis for vision in retinoblastoma survivors is good. This approach helps avoid unnecessary screening. one vision. Rivera-Luna R. de Souza Reis R. Amador-Zarco J. Invest Ophthalmol Vis Sci 2006 May. Clin Transl Oncol 2006 Jan. and subsequent examinations can be arranged with ophthalmic units familiar with retinoblastoma management. 90% cases are sporadic. Parulekar / Early Human Development 86 (2010) 619–625 the mutation. Bilateral cases are alwaysgermline. • Screening of at risk relatives is recommended to enable early detection. Haik BG. Occasionally however. Ordaz JC. 18.111(1):96–102. de Oliveira Santos M. Ribeiro RC. and osteogenic or soft tissue sarcomas. External Beam Radiotherapy is reserved for resistant cases.1. Prognosis 15. [4] Abramson DH. Cancer genetics. Metastases may occur several decades after the initial presentation. Key guidelines • If diagnosed early and treated appropriately.104(1):43–7. • Leucocoria and squint are the commonest presenting features. [1] Leal-Leal CA.

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