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 Ó 2012 Saudi Ophthalmological Society, King Saud University. All rights reserved. http://dx.doi.org/10.1016/j.sjopt.2012.03.002 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 inhibi- tors 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 reti- nal 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

Load more