Retinoblastoma Major Review with Updates on Middle East Management Protocols

Saudi Journal of Ophthalmology (2012) 26, 163–175

Ophthalmic Pathology Update

Retinoblastoma major review with updates on Middle East management protocols

⇑ Ihab Saad Othman, MD, FRCS

Abstract

Many advances in the field of management of retinoblastoma emerged in the past few years. Patterns of presentation of retinoblastoma in the Middle East region differ from Western community. The use of enucleation as a radical method of eradicating advanced disease is not easily accepted by patient’s family. We still do see stage E, failed or resistant retinoblastoma and advanced extraocular disease ensues as a result of delayed enucleation decision. In this review, we discuss updates in management of retinoblastoma with its implication on patients in our part of the world. Identifying clinical and high risk characteristics is important prognostically and are discussed for further management of retinoblastoma cases.

Keywords: Retinoblastoma, Staging, Classification, Histopathology, Middle East

Introduction cases is 100–120 cases/year.3 In a recent report from Jordan, the mean age-adjusted incidence of retinoblastoma was 9.32 Retinoblastoma is the commonest primary ocular malig- cases per million children per year for children aged 0– nancy of childhood originating from primitive retinoblasts 5 years.4 Retinoblastoma constituted 4.8% of childhood can- with tendency towards cone differentiation. Retinoblasts cer treated over 10 years at the National Cancer Institute in arise from the inner neuroepithelial layers of the embryonic Sudan and presented in an advanced stage in 16 out of 25 re- optic cup.1 The incidence of retinoblastoma ranges from 1/ ported cases.5 15,000 to 1/20,000 live births with an annual incidence in children younger than 5 years of 10.9/million. Two distinct forms of retinoblastoma are present namely sporadic and familial Genetics (Table 1). Most presenting cases are unilateral sporadic. Only 33% of cases are bilateral and all (100%) are hereditary while To properly understand the role of retinoblastoma gene, it 15% of unilateral cases presenting with unilateral multifocal is important to revisit the normal cell cycle which represents tumors are hereditary. Familial cases represent 10% of cases the different phases of cell proliferation. Most cells of the and 90% of cases are presenting before age 4 years.1,2 In body are in a G0 phase which is a quiescent phase where cells Egypt, after reviewing 321 new cases of retinoblastoma over contain active hypophosphorylated form of retinoblastoma 5 years at the National Eye Center and the Eye and Laser protein. When there is need for cell division, the cells go into World Center, the estimated number of new retinoblastoma G1 phase which is a presynthetic growth phase 1 where the

Received 7 February 2012; received in revised form 7 March 2012; accepted 7 March 2012; available online 16 March 2012.

National Eye Center, Rod El-Farag, Cairo, Egypt Eye and Laser World center, Giza, Egypt Ophthalmology Department, Kasr EL-Ainie Medical School, Cairo University, Egypt

⇑ Address: 6 Tahrir Street Dokki, Giza, Egypt. Tel.: +20 2 3762 7771; fax: +20 2 3762 8753. e-mail address: [email protected]

Peer review under responsibility Production and hosting by Elsevier of Saudi Ophthalmological Society, Access this article online: www.saudiophthaljournal.com King Saud University j www.sciencedirect.com 164 I.S. Othman cells contain active hypophosphorylated form of retinoblastoma protein. S phase is a DNA-synthetic phase. G2 phase is a premitotic growth phase 2. M phase is a mitotic phase resulting in duplication of the dividing cell.6 Cyclins are regulatory proteins controlling the cell cycle. Their regulatory function is accomplished by binding and activating CDKs (cyclin dependent kinases). CDKs control the important transition points in cell cycle through phos- phorylation or dephosphorylation of other proteins. Cyclin- CDK complexes are regulated by the binding of CDK inhibitors which are important in regulating cell cycle check points from G1 to S phase.6–8 At this checkpoint, the cell ensures a flawless DNA replication with all errors repaired before progression to cell division. This checkpoint is guarded by retinoblastoma protein in its active hypophosphorylated form (Fig. 1). Tumor virus transforming proteins (adenovirus EIA, simian virus 40 (SV40) antigen, large T and human papilloma virus [HPV-E7]) induce tumors by binding to and inactivating 9 the active form of Rb protein. Some oncoviruses (SV4O, Figure 1. Growth cycle: most cells of the body are in G0 or quiescent HPV, adenovirus) are thought to produce cancer by making stage. When they start cell division, they pass through G1, S, G2 and M proteins that complex and inactivates the suppressor protein phases. Retinoblastoma protein (Rb) in its active hypophosphorylated product of the RB gene.10 The Rb protein unable to bind to form acts on the checkpoint from G1 to S phase to ensure flawless DNA E2F transcription factor is functionally deleted with subse- replication. quent loss of cellular ability to be inhibited by antigrowth signals (Fig. 2). Additionally, RB primary tumors harbor cells with expression of stem cell markers namely CD44 and retinal progenitor markers, PROX1 and syntaxin 1A.11 Presence of these neural stem cells among others could make the tumor more aggressive in behavior or metastases, reactive after a quiescent dormant period or more resistant to anti- cancer therapy.12 The ability of the tumor to be invasive may be explained by the presence of expression of endothelial nitic acid synthases (eNOS) and specially the inducible nitric acid synthases (iNOS).13 Degradation of basement membrane by matrix metalloproteinases (MMPs) is one of the most critical steps in various stages of tumor progression, including tumor angiogenesis, tumor growth, and also local invasion and subsequent distant metastasis.14 Adithi et al.15 have demon- strated higher expressions of EMMPRIN, MMP-2 and MMP- 9, and TIMP-1 and TIMP-2 in invasive RB tumors. Poorly differentiated tumors showed higher expression of MMP-2 than tumors that were moderately or well-differentiated tumors. The expression of TIMP-1 and TIMP-2 was higher in

Figure 2. Inactivation of Rb protein by hyperphosphorylation results in uncontrolled cell replication.

Table 1. Main differences between sporadic and familial retinoblastoma. Sporadic Familial retinoblastoma invasive tumors. With respect to differentiation, there were retinoblastoma higher expressions of TIMP-1 and TIMP-2 in poorly differenti- Incidence 90% 5–10% ated tumors, as compared to moderately and well-differenti- 1/100,000 child ated tumors. Epithelial cell adhesion molecule (EpCAM) is Mean age of 30 12 presentation highly expressed in RB tumors with invasion compared to tu- 16 (months) mors without invasion. EpCAM plays a role in increased cel- Mutation Somatic: the Germline: the mutation is lular proliferation of RB cells and can be considered a mutation is only in normal cells in the body potential target molecule in the therapeutic interventions in retinoblasts and in retinoblasts Laterality Unilateral Bilateral 70% for RB management. Protein 53 (p53) controls powerful stress unifocal May be unilateral but response as it integrates upstream signals from many types of multifocal 30% DNA damage and inappropriate oncogenic stimulation, all of Second cancers No higher risk Increased risk which lead to p53 activation and subsequent regulation of Genetic No Yes genes involved in cell cycle arrest or apoptosis.17 Proteomics transmission has contributed significantly in understanding the biology of Retinoblastoma major review with updates on Middle East management protocols 165

RB tumors by revealing altered protein expression in tumor bers affection by the disease and to emphasize the impor- cells. The altered proteins belong to different categories such tance of early postnatal screening.1 Genetic risk for as apoptosis, cell proliferation, signal transduction, meta- affected siblings is presented in Table 2. bolic, and active transport processes. PRDX6 and CRYAA could be potential targets in the clinical management of RB.18 Diagnosis

The retinoblastoma gene: a tumor suppressor Ninety percent of retinoblastoma cases are presenting be- anti-oncogene low the age of 4 years. Restriction fragment length polymor- phisms performed on chorionic villus sampling or Retinoblastoma (RB1) gene is located on the long arm of amniocentesis cultured cells.23 Additionally, during in vitro chromosome 13 (13q14 band). This gene is inherited as an fertilization, absence of preimplantation genetic diagnosis autosomal dominant disease; however it is a ‘‘recessive tu- of retinoblastoma gene mutation allowed pregnancies of a mor suppressor gene’’ at the cellular level. RB gene sequence fetus without retinoblastoma.24 contains 180,388 base pairs. The Rb gene protein product Diagnosis at 1 month of age is highly positive in absence (928 amino acids) is a DNA-binding protein found in the nu- of leucocoria in patients with family history of retinoblastoma cleus of every cell in the body. The DNA-binding protein ex- whether a parent or a sibling is affected (Fig. 4A).25 ists in an active hypophosphorylated and an inactive Typically, intraocular retinoblastoma manifests as leucoco- hyperphosphorylated state. Rb protein is involved in control ria (90%) and strabismus (35%). More advanced disease pre- of the cell cycle (necessary for terminal differentiation). When sents with buphthalmos, fixed dilated pupil, spontaneous active, Rb protein prevents advancement of cells from G1 to hyphema, NVG and heterochromia iridis. Flat retinoblastoma S phase of the cell cycle (Fig. 1). When the cells are stimu- presents in elderly as a pseudohypopyon. When the tumor lated by growth factors, RB protein is inactivated by phos- outgrows its blood supply and becomes necrotic, it presents phorylation allowing the cells to go from G1 to S phase.7,19 Once in S phase, cells are committed to divide without additional growth factor stimulation with lack of terminal differentiation meaning cancer development. Absence of RB protein or loss causes continual cell division into S phase with lack of terminal differentiation meaning cancer development and metastasis (Fig. 2). This requires inactivation of both copies of the RB1 gene.20,21

Retinoblastoma gene inheritance

The retinoblastoma (RB) gene is inherited as an autosomal dominant disease. However at the cellular level it is a ‘‘recessive tumor suppressor gene’’. Normal individuals have two functional copies of the RB gene (RB, RB). Familial cases are hemizygous for retinoblastoma gene (RB, rb) ‘‘first hit’’ containing one functional and one inactivated gene, in all cells of the body. A single functional gene prevents malignant transformation. Tumors develop when the ‘‘second hit’’ is acquired as a somatic event in the developing retinal cell, thus both normal suppressor genes in a single retinal cell are lost or inactivated (rb, rb). The absence of the gene product in the homozygous state leads to the development of retinoblastoma (rb, rb). In the hereditary form two mutations occur, in both a prezygotic cell and a postzygotic cell. First mutation occurs usually in a sperm or an ovum. All somatic cells are affected by the first hit. Second mutation occurs in a somatic retinal cells resulting in multifocal unilateral or bilateral disease or both (Fig. 3).1 Second mutation may affect other cells of the body resulting in pineal tumors, sarcomas, breast and lung cancers.22 Tumors in cases of familial retinoblastoma are frequently bilateral multifocal or unilateral mul- ticentric (15% of cases). Sporadic somatic retinoblastoma result from the sequen- tial inactivation of both genes in a single retinal cell in a patient whose genotype is normal (RB, RB). Both hits are acquired events (occur in a post-zygotic somatic cell), Figure 3. Hereditary or genetic mutation starts in a sperm ‘‘first hit’’ (red explaining the later onset and unilaterality of the disease. chromosome in the sperm). This results in a zygote with loss of one allele It is important to counsel the family members affected by of RB gene. A second hit (arrow) occurs in a retinoblast resulting in tumor retinoblastoma about the probability of other family mem- formation. All cells of the body carry a hemizygote state of RB. 166 I.S. Othman

Table 2. Genetic counseling: risk that subsequent child will have spontaneous growth arrest and or involution leaving a retinoblastoma. partially calcified scar without any previous treatment. This Unilateral retinoblastoma tumor behaves genetically as hereditary retinoblastoma and Affected parent with no affected children 3% follow up is warranted as the tumor may transform to actively Normal parents, one affected child 3% growing retinoblastoma. Primary phthisical eyes harbouring One affected parent, one affected child 30% retinoblastoma are often associated with bilateral disease. Bilateral retinoblastoma Enucleation of primary phthisical eyes is recommended One affected parent, no affected child 40% Normal parents, one affected child 10% as residual viable tumor cells with characteristics of poorly One affected parent, one affected child 50% differentiated retinoblastoma was noted in a majority of cases.28 as an orbital cellulitis-like picture. Extraocular retinoblastoma High risk factors associated with retinoblastoma is still encountered in our part of the world mainly due to delay in diagnosis, delay in treatment and patients refusal of pri- It is important to identify high risk factors associated with mary or secondary enucleation as a curative modality. retinoblastoma recurrence or metastasis. Clinical high risk Proptosis is related to an orbital tumor due to massive extra- factors include extensively necrotic retinoblastoma which is scleral extension or a fungating mass through corneal perfo- found to be associated with extraocular extension, optic ration. Preauricular and submandibular lymphadenopathy nerve invasion, or choroidal invasion.29 Older age, longer and systemic metastases involving bones, or bone marrow, lag period, hyphema, pseudohypopyon, staphyloma, and meninges, paranasal sinuses, salivary glands, lymph nodes, orbital cellulitis are other important high risk factors.30 Delay subcutaneous tissue, liver, spleen, pleura, and testes.1 A spe- in enucleation of more than 3 months after diagnosis and the cial entity of retinoblastoma is the trilateral retinoblastoma, use of pre-enucleation chemotherapy in group E eyes with where bilateral intraocular disease presents with a pineal advanced retinoblastoma downstaged pathologic evidence gland tumor and suprasellar/parasellar neuroblastic tumors of extraocular extension, and increased the risk of metastatic and primitive neuroectodermal tumor.26 This is less com- death from reduced surveillance and inappropriate manage- monly seen in the era of systemic chemotherapy use.27 ment of high-risk disease.31 Elevated intraocular pressure and Another rare entity is the spontaneous regression or arrest buphthalmos are also associated with high risk pathological of retinoblastoma which represents a tumor that undergoes features.32

Figure 4. Hereditary retinoblastoma diagnosed in the sibling at age 2 weeks OS. Child underwent chemoreduction with focal therapy. B: initial good response after laser transpupillary thermotherapy. C: Tumor recurrence. D: tumor ablation following Ruthenium-106 plaque application. Tumor controlled at 60 months follow up. Retinoblastoma major review with updates on Middle East management protocols 167

In submitting the enucleated globe for histopathology, the ceous cell carcinoma, squamous cell carcinoma, and malig- ophthalmic pathologist should comment on several high risk nant melanoma have also been recognized as well as brain factors which have significant implications on patient survival. cancer.37 The mean latency period for the appearance of Pathological high risk factors include: Retinoblastoma with the second primary is approximately 13 years. Patients who invasion into the postlaminar optic nerve and/or posterior survive a second tumor are at risk for a third, fourth, and even uvea which is found to be a high risk for metastasis and fifth nonocular tumor.38 Carriers of mutant or deleted RB1 death.33 Retrolaminar optic nerve invasion and massive uveal who did not receive high-dose radiotherapy have a much invasion (defined as >3 mm in diameter), scleral invasion with higher lifetime risk of common epithelial cancers, particularly iris neovascularization and neovascular glaucoma are other cancers of the lung, bladder and, probably, breast, than of high risk factors (Fig. 5).34 In presence of histopathological sarcomas and other early-onset cancer. Most of the excess high risk factors, postenucleation chemotherapy use was cancer risks in hereditary retinoblastoma survivors may be effective in preventing metastasis.33,35 preventable by limiting exposures to DNA damaging agents (radiotherapy, tobacco, and UV light).39 Regarding associa- Systemic cancer tion of chemotherapy with development of second cancer, Gombos et al.,40 reported in their retrospective study that It is now recognized that a child with retinoblastoma has there was a high incidence of secondary acute myelogenous approximately a 5% chance of developing another malig- leukemia in retinoblastoma patients after chemotherapy with nancy during the first 10 years of follow-up, 18% during the topoisomerase II inhibitors (etoposide), where 12 out of 15 first 20 years, and goes up to 44% at age 45 years.36,37 The cases of their cohort had received topoisomerase II inhibitors. 30-year cumulative incidence is approximately 35% or even higher for those patients who received radiation therapy Diagnosis of retinoblastoma (external beam therapy) compared with an incidence rate of 6% for those patients who avoided radiation. Osteogenic sar- Diagnosis of retinoblastoma depends on the stage of dis- coma, often involving the femur, is the most common, but ease presentation. Small intraretinal tumors manifest as other tumors such as spindle cell sarcoma, chondrosarcoma, innocuous grayish white or translucent lesions in the neuro- rhabdomyosarcoma, neuroblastoma, glioma, leukemia, seba- sensory retina. With increase in size, fluid starts to accumulate

Figure 5. High risk factors with retinoblastoma. (A) Gross section showing massive choroidal invasion (>3 mm) with optic nerve invasion. (B) Photomicrograph showing scleral invasion (block arrow) with estrascleral invsion (asterisk) (H&E. original magnification 100). (C) Optic nerve section showing malignant round blue cells invasion beyond lamina cribrosa (arrow). 168 I.S. Othman around the tumor as exudative retinal detachment and the peated CT scans are better avoided in bilateral cases as it ex- tumor acquire an enlarging caliper feeder artery and draining poses the body to a radiation dose. vein. The tumor shows intra-lesional calcification in 80–90% of cases. Retinoblastoma tumors can grow towards the vitre- Staging of retinoblastoma ous cavity and is known as endophytic tumor, where due to discohesiveness of the tumor cells, it easily spread in the vit- Several classifications of retinoblastoma have been devel- reous cavity and anterior chamber. Otherwise, the tumor may oped to assist in prediction of globe salvage. The most pop- grow towards the RPE into the subretinal space and is known ular grouping is the Reese-Ellsworth classification which as exophytic tumor inducing an exudative retinal detachment classified eyes according to quantity and location of the tu- and pushing the retina anteriorly in the vitreous cavity. Other mor(s) and its associated features such as vitreous seeding. growth patterns include a diffuse flat infiltration pattern Their goal was to create a method of predicting success of where the retina becomes slightly thickened by presence of external beam radiotherapy for retinoblastoma.42 Similarly, tumor cells without any tumefaction pausing a myriad of clin- the International Intraocular Retinoblastoma Classification ical dilemma in diagnosis like uveitis or pseudohypopyon. (IIRC) was created to assess outcomes in standardized proto- Less frequently, the presenting feature can be, hyphema, sec- cols of chemotherapy with focal consolidation therapy for ret- ondary to iris neovascularization, vitreous hemorrhage, or inoblastoma. Those involved in drafting the IIRC reached 1 signs of orbital cellulitis. scientific consensus at the 2003 International Retinoblastoma Symposium in Paris (Table 4).43 A new system of classification for retinoblastoma has recently been introduced by the Differential diagnosis American Committee on Cancer (2009) using the TNM system to classify the tumor7. This classification system de- There is a long listing of differential diagnosis of retinoblas- scribes both clinical (c-TNM) and pathological (p-TNM) toma. In an oncology referral practice, 48% of lesions referred classifications and accounts for both intraocular and extraoc- to as retinoblastoma proved to be pseudoretinoblastoma.41 ular disease. Adopting the TNM classification system would Table 3 shows the most common simulating lesions with their allow for the proper interpretation of results of future clinical differentiating points.1 trials. It is vital that the classification be instituted exactly as intended, and its use is now mandatory when publishing in 44 Investigations important peer-reviewed journals (Table 5).

Once the diagnosis is established, the patient may under- Management of retinoblastoma go ultrasonography showing tumor size and intrinsic calcification, Retcam fundus picture, fluorescein angiography (early Priorities in management of intraocular retinoblastoma are vascularity and late hyperfluorescence of the tumor), detailed tumor control. By controlling the tumor, the ophthalmic fundus drawings, laboratory work, and an audiogram to oncologist saves human life. Of course, the optimum method check the general status of the patient and effects of sys- for tumor control is to save the eye and vision. Unfortunately, temic chemotherapy when instated. MRI scans is ordered with advanced disease, the eye has to be sacrificed by enu- to delineate the extent of intraocular spread, optic nerve cleation. This should be carried out with no hesitation in or- and scleral/orbital invasion and to exclude pineal gland tu- der to save human life. mors. It is contraindicated to perform fine needle aspiration The therapeutic approach depends on staging of the dis- biopsy or open vitrectomy in any suspected retinoblastoma ease, laterality, systemic status, metastatic potential, and risk case as this will result in extraocular tumor dissemination. Re- of second cancer. Treatment is usually prolonged over many

Table 3. Common disease in the differential diagnosis of retinoblastoma. Lesion Unilateral Bilateral Age Comments Retinoblastoma Yes Yes 18 mo Calcium on ultrasound Toxocariasis Yes No 6–11 yr CT contact with puppies Negative ELISA excludes PHPV Yes No At birth Eye typically microphthalmic with inward-drawn ciliary processes, iris Shunt vessels Coats’ disease Yes RARE 18 MO-18 YR 21Ys male, ST quadrant (End 1st decade) leaky telangiectatic RD Vessels. Exudative with lipid. Massive exudation. ROP No Yes In infancy, but RX Oxygen not congenital Retinal dysplasia – Yes Congenital Microphthalmia, most 13 trisomy Incontinentia Yes Infancy Bullous skin eruptions, pigmentation Pigmenti Retinal Vascular abnormalities, dental and CNS abnormalities, X-linked dominant (lethal in males) 20 retinal detachment Norrie’s disease – X Congenital Males, X-linked recessive, Deafness, mental retardation Norrin (gene product) Medulloepithelioma X – 4 yrs ‘‘Diktyoma’’, benign and malignant, Teratoid and nonteratoid. Teratoid tumors, contain cartilage, muscle, brain, most ciliary body Retinoblastoma major review with updates on Middle East management protocols 169

Table 4. International retinoblastoma symposium (Paris, 2003). Group A All tumors are 3 mm or smaller, confined to the retina and at least 3 mm from the foveola and 1.5 mm from the optic nerve. No vitreous or subretinal seeding is allowed Group B Eyes with no vitreous or subretinal seeding and discrete retinal tumor of any size or location. Retinal tumors may be of any size or location not in group A. Small cuff of subretinal fluid extending 65 mm from the base of the tumor is allowed Group C Eyes with focal vitreous or subretinal seeding and discrete retinal tumors of any size and location. Any seeding must be local, fine, and limited so as to be theoretically treatable with a radioactive plaque. Up to one quadrant of subretinal fluid may be present Group D Eyes with diffuse vitreous or subretinal seeding and/or massive, nondiscrete endophytic or exophytic disease. Eyes with more extensive seeding than Group C. Massive and/or diffuse intraocular disseminated disease may consist of ‘greasy’ vitreous seeding or avascular masses. Subretinal seeding may be plaque-like, includes exophytic disease and >1 quadrant of retinal detachment Group E Eyes that have been destroyed anatomically or functionally with one or more of the following: Irreversible neovascular glaucoma, massive intraocular hemorrhage, aseptic orbital cellulitis, tumor anterior to anterior vitreous face, tumor touching the lens, diffuse infiltrating retinoblastoma, phthisis or pre-phthisis

Table 5. Definitions of tumor, node and metastasis. Clinical classification (cTNM) Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumors no more than 2/3 the volume of the eye with no vitreous or subretinal seeding T1a: No tumor in either eye is greater than 3 mm inlargest dimension or located closer than 1.5 mm to the optic nerve or fovea (coinciding with IIRC Group A) T1b: At least one tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea. No retinal detachment or subretinal fluid beyond 5 mm from the base of the tumor (coinciding with IIRC Group B) T1c: At least one tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea, with retinal detachment or subretinal fluid beyond 5 mm from the base of the tumor (coinciding with IIRC Group C) T2 Tumors no more than 2/3 the volume of the eye with vitreous or subretinal seeding Can have retinal detachment T2a: Focal vitreous and/or subretinal seeding of fine aggregates of tumor cells is present, but no large clumps or ‘‘snowballs’’ of tumor cells (coinciding with IIRC Group C) T2b: Massive vitreous and/or subretinal seeding is present, defined as diffuse clumps or ‘‘snowballs’’of tumor cells (coinciding with IIRC Group D) T3 Severe intraocular disease T3a: Tumor fills more than 2/3 of the eye(coinciding with IIRC Group D) T3b: One or more complications present, which mayinclude tumor-associated neovascular or angle closure glaucoma, tumor extension into the anterior segment, hyphema, vitreous hemorrhage, or orbital cellulitis (coinciding with IIRC Group E) T4 Extraocular disease (detected by imaging studies) T4a: Invasion of optic nerve T4b: Invasion into the orbit T4c: Intracranial extension not past chiasm T4d: Intracranial extension past chiasm Regional lymph nodes (N) NX: Regional lymph nodes cannot be assessed N0: No regional lymph node involvement N1: Regional lymph node involvement (preauricular, cervical, submandibular) N2: Distant lymph node involvement Metastasis (M) M0 No metastasis M1 Systemic metastasis M1a: Single lesion to sites other than CNS M1b: Multiple lesions to sites other than CNS M1c: Prechiasmatic CNS lesion(s) M1d: Postchiasmatic CNS lesion(s) M1e: Leptomeningeal and/or CSF involvement

months requiring repeated visits for active management and Currently available treatment methods for retinoblastoma lifelong follow up. In our area of the world, the socioeconomic include intravenous chemoreduction, diode laser thermo- status of the patient has to be considered in decision making therapy, cryotherapy, plaque radiotherapy, external beam and its ability to commit. If the decision comes to enucleation, radiotherapy, enucleation, orbital exenteration, and systemic it is important to spend time explaining to the parents the chemotherapy for metastatic disease.44 Unilateral retinoblas- necessity and the drawbacks of delaying the decision on the toma usually present at a late stage and are generally man- life of the child and to answer every question in the mind of aged with enucleation if the eye is classified as stage E; for the parents about cosmetic rehabilitation of the child. those eyes in groups A to D, chemoreduction or focal 170 I.S. Othman measures are used. For bilateral retinoblastoma, chemore- applied to cover the whole tumor surface with a safety mar- duction is utilized in most cases even if one eye is harboring gin around it. Usual set up of the laser machine is 10 min an advanced disease. Enucleation decision is delayed till the and the large spot laser indirect ophthalmoscope is applied end of six cycles and active focal management of the more over the lesion for sometime and moved slowly to cover advanced eye is usually carried out after the second cycle the tumor aiming at seeing a delayed onset grayish white of chemotherapy, along with focal treatment of the less ad- reaction, thus ensuring significant in-depth tumor penetra- vanced eye. tion. It is important to spend time treating tumors with subtle dispersed retinal seeds (Fig. 4B). Chemoreduction Plaque radiotherapy is used as a primary or more com- monly a secondary treatment modality for tumors that fail Systemic chemoreduction is given to the patients in order other focal therapies, even those that reach a moderate size, to reduce tumor volume to allow for therapeutic measures to up to 8 or 10 mm in thickness. We use Ruthenium/Rhodium- be more focused, effective and affecting less of the retinal tis- 106 applicators which are mainly emitting Beta irradiation sues not harboring tumor anymore.46 Systemic chemother- up to a tumor thickness of 6–7 mm after placing the plaque apy regimen for chemoreduction of retinoblastoma is not over the sclera to cover the tumor base with an extra 2– 47,48 49 50–53 uniformly agreed upon. One, two, three, and even 3 mm of safety margin. Different plaque diameters exist up 54 four drug regimen have been used with almost similar re- to 25 mm wide. The radiation dose to the tumor apex is sults in tumor control and ocular salvage. There is a general around 50 Gy delivered over a period of 2–5 days depending consensus about the use of systemic chemotherapy for six cy- on plaque activity. Tumor control rate following plaque radio- cles given every 3–4 weeks. Two-drug regimen of systemic therapy as a primary therapy or after failed chemothermo- chemotherapy using carboplatin and etoposide were found therapy is about 90%. Success decreases to 75% if plaque is 3 to have mild and reversible acute side effects in our study. used after tumor recurrence following external beam radio- The toxicity of vincristine reported to be in up to 40% of pa- therapy and mounts to 75% (Fig. 4 D).60 55 tients was avoided using this protocol. We use systemic Cryotherapy is applied for peripheral tumors under 3 mm chemotherapy regimen for six cycles given every 3–4 weeks in greatest dimension. A triple freeze thaw application is used to allow for adequate tumor reduction. Following two cycles insisting on seeing the ice ball beyond the apex of the tumor of systemic chemotherapy, most tumors shrink with a mean at each application. It is a critical modality for management of of 35% in tumor base and 50% in thickness with resolution recurrent subretinal seeds near the ora serrata. of subretinal fluid. Focal therapy to the individual tumors is usually delivered at cycle 2. With such a regimen, tumor con- External beam radiotherapy trol was achieved in 100% of group A eyes, 93% of group B eyes, 86% of group C eyes, 48.8% of group D eyes and 0% This modality uses photons delivered from a remote ma- for group E eyes. Our results for globe survival matched chine to the eye. EBRT has fallen out of use because of its lo- the reported literature in developing countries53,56,57 and cal complications effect and associated high incidence of approaching results of developed countries.49–52,54,55 second cancers in the irradiated zone years after cure from After finishing active management, follow up is warranted. the disease in hereditary forms of retinoblastoma. EBRT is The child is examined under anesthesia monthly to observe preserved only to bilateral advanced disease with diffuse vit- for new tumor development, marginal recurrence or seeds reous seeds as a last globe preserving modality in patients reactivation following the disappearance of the tumor inhib- refusing bilateral enucleation after failure of all other conser- iting effect of chemotherapy. Focal therapy is delivered vative treatment modalities. We should specify to radiologist according to the situation, and the follow up is kept monthly to give a ‘‘whole eye technique’’ to cover the diffuse vitreous as long as active management is performed. Recurrent tu- seeds when radiotherapy is required. A ‘‘lens sparing tech- mors, new tumors or retinal seeds recur in the first 2 years nique’’ might give adequate control if combined with focal after treatment and it is crucial to early detect and properly therapy to cover the peripheral tumors at the ora serrata.61 manage recurrences.58,59 External beam radiotherapy may induce a second cancer in the field of irradiation, and this was the driving force behind Focal therapies the use of systemic chemotherapy for chemoreduction that is largely replaced external beam radiotherapy.36–38,62 Focal therapies include transpupillary diode laser thermotherapy (TTT), cryotherapy, and plaque radiotherapy. Com- Subconjunctival chemoreduction for retinoblastoma monly, focal therapies are applied to an eye while the child is receiving chemoreduction, and they are repeated to each Increasing interest has emerged in delivering chemother- tumor at each chemotherapy session. We insist on delivering apy locally to the eye while minimizing systemic exposure. focal therapy the same day or the day before chemotherapy Chemotherapy has been given as posterior subtenon carbo- to enhance the synergistic effect of thermotherapy to platin injection (20 mg/2 cc)63 or carboplatin given as a nano- chemotherapy.59 molecule.64 Periocular topotecan is injected in a fibrin The goal is to deliver a temperature of 42–60 °C, a tem- sealant65 or as an episcleral implant.66 Other delivery systems perature that is below the coagulative threshold and thus included depot gels,solid polymers, miniature catheters sparing the retinal vessels of photocoagulation. The combi- placed adjacent to the sclera and iontophoresis systems.67 nation of heat and chemotherapy is termed chemothermo- Local side effects include inflammation, ptosis, scarring and therapy. Power settings depend on the tumor thickness loss of sight.67 with thinner tumor receiving less power. Usual range of Posterior subtenon periocular boost of subconjunctival power settings with diode laser TTT is from 300 to 800 mW chemotherapy is given in advanced retinoblastoma in both Retinoblastoma major review with updates on Middle East management protocols 171 eyes or in their only remaining eye along with systemic was 30%. Three injections at monthly intervals were given chemoreduction. and subretinal and vitreous seeds recurrence was noted at one year follow up necessitating enucleation.74 The minimum age with successful cannulation was Selective intraophthlamic artery melfalan injection 3 months and the main drug used is melfalan, at a dose of (0.35 mg/kg) or 5–7.5 mg/injection. Other additional drugs Japanese investigators have been using an interventional include topotecan and carboplatin depending on the stage radiology technique of infusing melfalan into the carotid ar- of the disease and tumor response.69 tery for retinoblastoma since 1988. Their technique used a Reported complications include transient eyelid edema, balloon catheter inserted into a femoral artery puncture blepharoptosis, cilia loss, and orbital congestion with tempo- and a (balloon) catheter that was passed into the internal car- rary dysmotility. Vascular events are of concern and include otid artery and inflated to occlude the internal carotid artery ophthalmic artery stenosis (permanent or temporary). Con- (for as long as 30 min) beyond the orifice of the ophthalmic comitant central or branch retinal artery occlusion (perma- artery, allowing chemotherapy infused into the cervical inter- nent or temporary). Retinal pigment epithelial mottling with nal carotid artery to perfuse the eye selectively without per- development of later-onset underlying choroidal atrophy. fusing the brain. In 1452 procedures of 1469 trials, the eye Sectoral choroidal occlusive vasculopathy leading to chorio- preservation rate was 100% in group A, 88% in group B, retinal atrophy was also observed (Fig. 7). There was no evi- 65% in group C, 45% in group D, and 30% in group E accord- dence of metastasis, stroke, brain injury, or persistent ing to the International Classification of Intraocular Retino- systemic toxic effects.75,76 blastoma. Two eyes (0.5%) developed severe orbital In a study of enucleated globes following intraarterial inflammation, and 2 eyes (0.5%) had diffuse chorioretinal melfalan, showed a range of tumor response from complete atrophy. Transient periocular swelling or redness occurred regression to no regression with viable tumor. Ischemic atro- in some cases. No severe systemic adverse events were de- phy involving the outer retina and choroid was noted, with tected. Transient bronchospasm occurred in 1 patient 68 foreign intravascular foreign material resembling granuloma- (0.3%), and transient vomiting occurred in several patients. tous reaction observed within occluded vessels.77 In 2008, Abramson et al., reported preliminary results of a Selective ophthalmic artery melfalan injection is a promis- modified technique by directly injecting melfalan into the ing new technique. We have been using this technique to ophthalmic artery using a microcatheter. The goal was to treat 20 patients with advanced stage D/E disease in addition achieve a targeted focal delivery of chemotherapy to the tu- to focal therapy (Othman et al., unpublished data). Two of the mor with minimal systemic complications and possibly more patients experienced ophthalmic artery occlusion (Fig. 7). Ele- efficacy. Since then, the technique has been adopted in many 69–71 ven of 15 cases of stage E disease and 2 out of 5 cases of stage centers worldwide. D ended up by enucleation. All cases were combined by focal Superselective ophthalmic artery infusion of chemother- therapy. It is our recommendation to cautiously use this tech- apy was used initially as an ocular salvage therapy in ad- nique for advanced disease as a last resort of therapy when vanced group V retinoblastoma as a primary and secondary the patient’s family is refusing enucleation as a primary and/ treatment modality. With more comfort of the technique, or secondary ocular salvage procedure. cannulation of one or both ophthalmic arteries with chemotherapy injection could be done via femoral artery cannulation and is used in less advanced disease stage as a Enucleation primary or secondary treatment modality. This technique seems to control advanced disease, subretinal seeds and vit- Enucleation is an important tool in management of retino- reous seeds whether primary or recurrent (Fig. 6).72,73 blastoma. It is indicated in advanced unilateral disease, stage A recent report showed that the globe salvage rate in E retinoblastoma, after failure of tumor control by other group E in eyes managed with intra-arterial chemotherapy modalities, or in eyes with secondary glaucoma, vitreous

Figure 6. (A) Vitreous seeds and inferonasal tumor recurrence following chemofocal therapy and external beam radiation for unilateral sporadic retinoblastoma. (B) Tumor and vitreous seeds control following 3 monthly injection of intraophhtlamic artery melfalan. 172 I.S. Othman

Advanced stage E unilateral disease is managed by enucleation as it is more likely to have elevated intraocular pressure, invasion of the anterior chamber, uveal tract, optic nerve and sclera on histopathological examination.80 In unilateral retinoblastoma, about 70% of cases are managed by enucleation due to late presentation. Our philosophy in management of bilateral cases was to initiate systemic chemoreduction using carboplatin and etoposide for six cycles, start to manage both eyes with focal therapy mainly from the second chemotherapy cycle, delaying the decision for enucleation of the advanced eye till the end of chemotherapy to assess the response and to perform enucleation when indicated using the largest possible orbital implant in a more suit- able environment for surgery. This practice might be associated with less orbital volume growth retardation through delaying enucleation beyond the first year of life.81,82 Figure 7. Ophthalmic artery occlusion with severe choroidal RPE mot- We agree with others regarding the importance of ade- tling following a second injection of ophthlamic artery melfalan. quate orbital volume replacement in pediatric population to obviate the need of further surgeries in adulthood.82 As a rule of thumb, we use an 18 mm diameter orbital implant hemorrhage, hyphema, pseudohypopyon. Enucleation is before 1 year of age and a 20 mm orbital implant after 1 year associated with placement of an orbital implant of adequate of age in orbital volume replacement. An 18 mm implant has size made of porous implants (hydroxyapatite, porous poly- a volume of 3.1 ml and a 20 mm implant replaces an orbital 83 ethylene, or aluminium oxide) or non-porous implants like volume of 4.2 ml. An enucleated globe has a volume of 84 polymethylmethacrylate sphere and silicone, wrapped in do- 5.5–9 ml depending on age and globe size. Both silicone nor sclera, or synthetic viryl mesh or directly placed in the or- implant and hydroxyapatite implants are used in our practice. bit with attachment of the 4 recti muscles around it using 6/0 There was no tumor progression under chemotherapy in our Vicryl sutures.78 Closure of conjunctiva should be in layers series even in eyes with advanced disease. A recent report starting by the tenon’s capsule then the conjunctival layer. indicated significant orbital growth retardation after enucle- The superior rectus muscle should not be tightened to the ation, even with a hydroxyapatite implant. Orbital growth muscle complex to avoid induced ptosis by pulling on the retardation was correlated with operation age and also more 82 rectus/levator complex and adding to the superior margin prominent in children treated in the first year of life. of the prosthesis, to restore functional length and create a more anatomic pivot point for the levator muscle.79 It is Pathologic staging important to check the integrity of the fornices and to put a conformer at the end of surgery. Handling the globe should If an eye is enucleated, pathology could provide histologic be done according to the following guidelines. verification of the disease and pathologic staging could

Table 6. Pathologic classification (pTNM). Primary tumor (pT) pTX Primary tumor cannot be assessed pT0 No evidence of primary tumor pT1 Tumor confined to eye with no optic nerve or choroidal invasion pT2 Tumor with minimal optic nerve and/or choroidal invasion: pT2a: Tumor superficially invades optic nerve head but does not extend past lamina cribrosa or tumor exhibits focal choroidal invasion pT2b: Tumor superficially invades optic nerve head butdoes not extend past lamina cribrosa and exhibits focal choroidal invasion pT3 Tumor with significant optic nerve and/or choroidal invasion: pT3a: Tumor invades optic nerve past lamina cribrosa but not to surgical resection line or tumor exhibits massive choroidal invasion pT3b: Tumor invades optic nerve past lamina cribrosa but not to surgical resection line and exhibits massive choroidal invasion pT4 Tumor invades optic nerve to resection line or exhibits extraocular extension elsewhere pT4a: Tumor invades optic nerve to resection line but no extraocular extension identified pT4b: Tumor invades optic nerve to resection line and extraocular extension identified Regional Lymph Nodes (pN) pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node involvement pN1 Regional lymph node involvement (preauricular, cervical) pN2 Distant lymph node involvement Metastasis (pM) cM0 No metastasis pM1 Metastasis to sites other than CNS pM1a Single lesion pM1b Multiple lesions pM1c CNS metastasis pM1d Discrete mass(es) without leptomeningeal and/or CSF involvement pM1e Leptomeningeal and/or CSF involvement Retinoblastoma major review with updates on Middle East management protocols 173 provide information complementary to the clinical staging. 6. 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