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| REVIEW ARTICLE |
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| Year : 2011 | Volume
: 4
| Issue : 3 | Page : 108-115 |
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Retinoblastoma: Recent trends A mini review based on published literature
Vikas Khetan1, Aditi Gupta1, Lingam Gopal2
1 Bhagwan Mahaveer Vitreoretinal Services, Sankara Nethralaya, 18, College Road, Chennai, India
2 Department of Ophthalmology, National University Health System, Singapore
| Date of Web Publication | 29-Dec-2011 |
Correspondence Address:
Vikas Khetan
Sri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, 18 College Road, Chennai - 600 006, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0974-620X.91265
 Abstract | | |
Retinoblastoma (RB) is the most common intraocular malignancy in children. Recently, there have been significant advances made in the molecular pathology and the management of the disease. Last decade has witnessed better understanding of the genetics of RB, the discovery of new tumor markers expressed by the RB tumors, the identification of high-risk histopathological factors following enucleation, and newer methods of treatment including periocular chemotherapy and superselective intraarterial chemotherapy. All these advances have translated in improved survival rates for the affected children, improved rates of eye salvage, and improved visual outcomes. This article briefly reviews these advances.
Method of Literature Search: Literature on the Medline database was searched using the PubMed interface. The search strategy included MeSH and natural language terms using the keywords mentioned. Reference lists in retrieved articles and textbooks were also searched for relevant references. Keywords: Chemotherapy, genetics, retinoblastoma, tumor biomarkers
How to cite this article:
Khetan V, Gupta A, Gopal L. Retinoblastoma: Recent trends A mini review based on published literature. Oman J Ophthalmol 2011;4:108-15 |
| Epidemiology | |  |
Although the worldwide incidence of the heritable form of retinoblastoma (RB) is remarkably constant, the incidence of unilateral nonheritable disease is increasing, especially in developing tropical and subtropical countries. [1],[2] This trend can be merely due to improved ascertainment of cases, or can be real, suggesting that there may be an increasingly common exposure to an environmental factor. [1] The possible factors implicated include viral etiology [human papillomavirus (HPV)] and dietary influences during pregnancy. [2] However, Gilison et al have disputed the viral etiology of RB. [3]
The HPV is implicated in the etiology of sporadic RB since the E7 protein of HPV inactivates unphosphorylated RB protein (pRb). [4] Recently, some HPV strains such as HPV 16, 18, 6a, 33, 11, 31, 35, and 51 have been described in fresh tumor tissue from a subset of RB patients. [5],[6] Mohan et al found that children younger than 18 months were significantly associated with the presence of HPV DNA compared with children above 24 months in Indian patients with unilateral RB. HPV DNA was present in 47% of the cases, and HPV16 was the most frequent. [6] In contrast, Gillison et al reported results regarding 40 fresh-frozen tumors in North American group of patients who were analyzed for the presence of HPV, adenovirus (HadV), and polyomavirus (BKV, JCV, and SV40) genomic DNA sequences by polymerase chain reaction (PCR). [3] All samples were negative for 37 HPV types and for all other viruses, indicating that neither HPV nor any other pRb-inactivating human DNA tumor viruses play a role in the etiology of RB, regardless of RB genotype. A recent study in Brazilian children with RB reported a low prevalence of HPV DNA in RB. [7] The authors did not find a statistically significant difference between the rates of DNA HPV prevalence among all tumor specimens and among normal retinal specimens, using a modified technique of microdissection. Another study of Asian Indians including 83 cases of unilateral RB in a population detected HPV DNA in 24% of RBs. [4] The authors stressed on the need of a multicentric study globally, to indisputably clarify the role of HPV in the etiopathogenesis of sporadic RB.
| Classification | | |
Since the Reese-Ellsworth classification was found to be a poor predictor for chemoreduction success, it is no longer used. [8] The international classification system for intraocular RB introduced in 2003 is now the accepted classification and is being used in the current Children's Oncology Group treatment protocols. A staging system for extraocular RB has been proposed and followed, although it may not be frequently pertinent in the areas like United States, where extraocular extension rates are low. [9]
There is now an American Joint Committee of Cancer classification of RB, classifying the clinical and pathological disease under the TNM staging system followed for the rest of the systemic malignancies. [10]
| Clinical Presentation | | |
Diffuse anterior infiltrating RB is being increasingly reported recently. [11],[12],[13],[14] This is a separate type of diffuse infiltrating RB. The imaging modalities such as ultrasound biomicroscopy and anterior segment optical coherence tomography are useful for such cases. [15],[16]
| Genetics | | |
The knowledge regarding the genetics of RB and of RB1 gene protein has expanded vastly. [17],[18] RB gene (RB1) works a tumor suppressor gene that is required for efficient cell cycle exit in proliferating retinal progenitor cells, and for appropriate maturation in differentiating rods. In the absence of RB1, progenitor cells continue to divide, and rods do not mature. [19] Mutations in the RB1 gene are being studied in detail. [20] Valverde et al found 932 reported mutations in RB1 gene available in a searchable database. [21]
Recent advances on the structure, expression, and function of RB1 gene were summarized by Liu et al. [22] It has been established that function of RB family proteins (pRb1/105, p107, pRb2/p130, collectively referred to as pocket proteins) is largely dependent on interactions with E2F transcription factors. Normal pRb binds to and inhibits the E2F transcription factors, thereby halting transcription of E2F target genes, which are responsible for cell cycle progression. Inactivation of pRb by phosphorylation, by mutation, or by the interaction of viral oncoproteins leads to a release of the repression of E2F activity, thus facilitating cell cycle progression. Recent research has shown that besides regulating the E2F transcription factors, RB1 is involved in numerous other biological processes such as apoptosis, DNA repair, chromatin modification, and differentiation. [23] Moreover, RB1 also possesses E2F-independent functions that contribute to cell cycle control. [24],[25] It is known that pRb-mediated repression of E2F activity involves the recruitment of a variety of transcriptional co-repressors and chromatin remodeling proteins, including histone deacetylases (HDACs), DNA methyltransferases, and Brg1/Brm chromatin remodeling proteins. Inactivation of pRb by sequential phosphorylation during cell cycle progression leads to a dissociation of these co-repressors from pRb. Recent research has also shown that small molecules that halt the phosphorylation of pRb prevent the dissociation of certain co-repressors from pRb, especially Brg1, leading to the maintenance of pRb-mediated cell cycle arrest. Such small molecules have anti-cancer activities and will also act as valuable probes to study chromatin remodeling and transcriptional regulation. [26]
The ongoing research also aims to identify genes other than RB1 that are undergoing genomic alteration in the RB tumors. For instance, the well-known oncogene N-myc (gain at chromosome locus 2p24) is amplified in 10% of human RB. [27] Adithi et al reported on the expression of p63 and p73 proteins in RB. [28] They reported that p63, p73, and their delta isoforms (truncated forms) were expressed in more than 50% of tumor samples. Delta p63 and delta p73 isoforms are known to have p53 pathway suppressive properties.
Retinoma (RN), a benign retinal lesion, is considered to be the precursor of RB. [29],[30],[31],[32],[33] Recently, it has been demonstrated that the two mutational events inactivating the RB1 gene are already present in RN. [31] A study by Dimaras et al in RN importantly clarified that the two hits in RB1 (M1-M2) do not inevitably cause a malignant phenotype but only genomic instability. [31] At some point, this instability can lead to further genomic rearrangements (M3-Mn) that result in tumor progression. Sampieri et al reported that MDM4 gain may be involved in the early transition from normal retina to RN, while MYCN and E2F3 progressive gain may represent driving factors of tumor progression. [29] These results suggest that increased genomic instability, including chromosomal aberrations and progressive gene amplification, accompanies the RN-RB transition. Similar findings were reported by Dimaras et al that progression from RN to RB is characterized by changes in the copy number of oncogenes such as MYCN (2p24.3), E2F3 and DEK (6p22), KLF14 (7q32), and MDM4 (1q32), as well as tumor suppressor genes CDH11 (16q21) and p75NTR (17q21). [31],[32],[33]
In one series, it was discovered that 65% of human RB have amplifications in the MDMX gene, which produces a protein involved in the degradation of the pRb and p53 protein products. [34] The authors provided evidence that RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected during tumor progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. They supported the idea that MDMX is a specific chemotherapeutic target for treating RB. [34]
Nutlin-3 is a small-molecule inhibitor of the MDM2/MDMX and p53 interaction, which leads to the nongenotoxic p53 stabilization, activation of cell cycle arrest, and apoptosis pathways. A series of recent studies have strengthened the concept that selective, nongenotoxic p53 activation by Nutlin-3 might represent an alternative to the current cytotoxic chemotherapy, in particular for pediatric tumors and hematological malignancies, which retain a high percentage of p53(wild-type) status at diagnosis. Although Nutlin-3 is currently in phase I clinical trial for the treatment of RB, its effects on normal tissues and cell types remain largely to be determined and will require further investigation in the future years. [35]
pRb also binds to HDAC, which results in silencing of transcription. HDAC inhibitors are being investigated as they may be particularly useful because they induce cytotoxicity to tumors selectively. Recently, it was demonstrated that certain HDAC inhibitors reduced cell survival in human RB cell lines and significantly reduced tumor burden in both rat and mouse models of RB. [36]
After knocking out the tumor suppressor RB1 gene in the tumor-prone retinal cells, RB has to progress into full-fledged malignancy. This is achieved by triggering oncogenes, which can help in multiplication of the tumor cells. Different cancers take different routes for progression based on genetic instability. Comparative genomic hybridization and microarray-based PCRs have been narrowed to a few oncogenes, which probably helps RB to progress. [37] KIF14 and E2F3 may represent important pro-oncogenes, which have been seen to be deregulated in most RB tumors. By real-time PCR, an overexpression of these two oncogenes was found in all tumors studied compared with fetal, age-matched, and adult retinas. [38] Phenotype correlations revealed a statistically significant increase in mRNA expression of KIF14 in patients at older age at diagnosis. [39]
| Tumor Biomarkers | | |
Indovina et al focused on the p16INK4A tumor suppressor gene because of its possible role in RB pathogenesis and its involvement in predisposition to familial cancer. They observed that p16INK4A was downregulated both in patients and their parents and that p16INK4A downregulation seems to be due to its promoter hypermethylation. They suggested that this alteration could be a novel marker of inheritable susceptibility to RB in young patients. [40] The study by Mallikarjuna et al provided a dynamic protein profile of RB tumors, which could provide clues to study the mechanisms of RB oncogenesis and possibly be developed as potential biomarkers for prognosis and therapy. [41] The authors studied the differential protein profile of RB tumors by a combination of two-dimensional gel electrophoresis to separate and visualize proteins and mass spectrometry for protein identification. They identified 27 differentially expressed proteins in RB compared with normal donor retinas. Two of the several proteins upregulated are alpha crystallin A (CRYAA) and peroxiredoxin 6 (PRDX6) which can inhibit apoptotic processes in tumor cells. Another recent study has shown that expression of CRYAA was inversely correlated with apoptotic index of RB tumor cells. [42] One of the major roles of alpha CRYAA is to preserve the integrity of mitochondria and restrict the release of cytochrome c, subsequently resulting in tumor growth through escape from apoptosis. The authors concluded that CRYAA expression may prevent apoptosis of neoplastic cells, and their suppression may be useful in controlling tumor growth. Anti-sense or nucleotide-based anti-CRYAA therapies may be tried to inhibit CRYAA expression in RB.
Adithi et al had earlier demonstrated higher expression of MMP-2 and -9 in RB tumors. [43] This could relate to the increased expression of PRDX6, a possible upstream molecule that may induce higher MMP expression in RB. Upon proving this fact in RB, PRDX6 can be considered instead of MMPs for targeted therapy. [44]
RB cells have been shown to express human embryonic stem cell markers in recent years. [45],[46] Mohan et al reported higher expression of ABCG2 (cancer stem cell surface marker) and MCM2 (neural stem cell marker) by invasive RB tumors. [47] It was also shown that ABCG2 is not only expressed in Hoechst-dim RB cells but is co-localized with human embryonic stem cell markers, such as Oct3/4 and Nanog as further indication of a stem-like cell phenotype. [48] Similar markers were later studied by Kim et al. [49] The authors found that in the RB tumor, ABCG2 was strongly expressed out of Wintersteiner rosettes, whereas MCM2 and vascular endothelial growth factor (VEGF) were strongly stained in the rosettes. Interestingly, the outer portion of the rosettes was positive for MCM2, and the inner portion of the rosettes was positive for VEGF.
Another study reported that 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), an analog of AMP, induced G1/G0 cell cycle arrest and inhibited proliferation of neural stem cells via phospho-Rb and cyclin D down-regulation. [50] Recently, Theodoropoulou et al reported that AICAR-induced activation of AMPK inhibits RB cell growth. [51]
Anti-angiogenic therapy targeting VEGF has been proposed as a promising new treatment strategy of RB. [52] Recent studies have demonstrated the suppression function on angiogenesis and tumor growth of RB by VEGF-targeted RNA interference [53] and bevacizumab-induced VEGF-blockage. [54] Another study suggested that pigment epithelium-derived factor (PEDF) suppressed RB tumor growth by blocking angiogenesis instead of a direct cytotoxic effect on tumor cells. Down regulation of VEGF expression in tumor cells was thought to represent a mechanism for the anti-angiogenic activity of PEDF. [55]
Recent reports have showed good results of glycolytic inhibitors (2-deoxyglucose) alone [56] and its combination with angiogenic inhibitors (anecortave acetate) [57] in significantly enhancing tumor control of advanced RB in the LH BETA T AG mouse model.
In addition, a recent study has demonstrated that RB primary tumors harbor cells that express stem cell marker, CD44 and retinal progenitor markers, PROX1, and syntaxin 1A. [58]
| Management | | |
Current treatments for intraocular RB include enucleation, systemic chemotherapy, external beam radiation therapy (EBRT), and focal treatment (with cryotherapy, laser photocoagulation, thermotherapy, or brachytherapy with iodine 125 or ruthenium 106 plaques). [59] Intravenous chemoreduction (chemotherapy followed by focal consolidative treatment) is the preferred treatment for most eyes classified as groups B-D, using the International Classification of Retinoblastoma. Unilateral group D eyes should be primarily enucleated especially if the chance of salvaging useful vision is not good. Chemoreduction plus subconjunctival carboplatin is the other treatment option for group D eyes. Treatment success reported with chemoreduction has been 100% of group A eyes, 93% of group B eyes, and 90% of group C eyes. [60] Group D eyes showed 48% success, but recent trend is to manage these eyes with additional subtenon's carboplatin. The most difficult eyes to treat are those with extensive RB classified as group E. These eyes are generally managed with enucleation. However, when both eyes are group E, an attempt to save at least one eye with chemoreduction is made. Shields and coworkers analyzed chemoreduction results in 76 group E eyes. [61]
They found that group E eyes treated with chemoreduction and low-dose prophylactic radiotherapy showed significantly fewer recurrences than those treated with chemoreduction alone.
COG has initiated a series of prospective multicenter trials to improve treatment outcomes with systemic chemotherapy. Although chemotherapy protocols vary slightly between the institutions, many centers are currently treating larger intraocular tumors with three-drug regimen with carboplatin, etoposide, and vincristine. Zage and associates found that two-agent chemotherapy with carboplatin and etoposide resulted in a vision salvage rate without EBRT of 77.3% in group A and B tumors, but only a 26.9% salvage rate in group C and D tumors. [62] Other studies have shown good results with carboplatin, etoposide, and vincristine (triple therapy), including higher doses of carboplatin used in some group C and D patients. [60]
The Toronto protocol of chemotherapy involves inclusion of cyclosporin along with the three drugs for groups B-D. Cyclosporine counteracts the multidrug resistance. [63]
Periocular chemotherapy has been tried for many drugs, [64],[65],[66] but carboplatin is the most widely used. [66] Subconjunctival carboplatin is also used as a treatment along with systemic chemotherapy with varying success worldwide. In 2007, COG opened a phase III clinical trial for periocular chemotherapy treatment using a sub-Tenon injection of carboplatin in group C and D patients. However, reports of toxicity using this approach have included ocular motility changes, fibrosis of orbital soft tissues, orbital fat necrosis, [67] severe aseptic orbital cellulitis, [68],[69] and ischemic necrosis and atrophy of the optic nerve resulting in blindness. [70] Recent trials have used a fibrin sealant formulated for controlled and sustained release of chemotherapy at the site of application. [71] This is useful to prevent the dispersion of a large amount of drug into the orbital tissues, thereby avoiding most of the associated complications. Topotecan in fibrin sealant subconjunctivally to treat RB has also been used successfully in a mouse model as well as in children with RB. [72],[73]
EBRT was replaced with chemoreduction for intraocular disease because of high risk of development of second malignancies, if administered before the age of 12 months. However, intravenous chemotherapy is also not without significant complications. Recently, Jehanne et al reported a low but significant risk of ototoxicity after carboplatin therapy, with serious consequences for two children requiring hearing aid who developed grade 4 toxicity. [74] Gombos et al report a small cohort of patients with RB in whom secondary acute myelogenous leukemia developed, associated with the administration of certain chemotherapeutic agents including topoisomerase inhibitors and alkylating agents. [75]
Present studies are focusing on selective delivery of chemotherapeutic agents to the eye, in an attempt to avoid systemic side effects of chemotherapy. Recently, localized intra-arterial chemotherapy (IAC) with delivery under fluoroscopy and selective ophthalmic artery infusion in RB patients has met with tentative success. Abramsons group reported good tumor regression [76] and persistence of retinal function [77] using IAC as primary treatment of RB, as well as in children with previously failed therapy. [78],[79],[80] Recently, the group published their 4-year results and reported that IAC is safe and effective in the treatment of advanced intraocular RB. [81] Many more reports showed good regression with the technique. [82],[83],[84],[85],[86] Furthermore, the rate of eyes that were enucleated was found to be higher when IAC was the secondary rather than the primary treatment. [87]
Vijayakrishnan et al reported that accumulated irradiation toxic effects following multiple sessions of IAC could be cataractogenic and possibly carcinogenic, especially in irradiation-sensitive patients with RB. [88] They recommended careful use of fluoroscopy during IAC with limited irradiation exposure. Munier et al reported the occurrence of potentially sight-threatening side effects, such as severe chorioretinal atrophy secondary to subacute choroidal occlusive vasculopathy or central retinal artery embolism after superselective ophthalmic artery chemotherapy for advanced intraocular RB. [89] Histopathology of enucleated eyes that were treated with IAC revealed that ocular complications including thromboembolic events could occur after IAC. [90]
Shields et al reviewed the available literature on the technique and concluded that IAC should be used with concern and it might take many more years before the true potential and complications of this technique are realized. [91] Recently, the authors reported the results of 17 patients treated with IAC. Globe salvage was achieved in 67% of eyes managed with IAC as primary treatment and 50% of those where IAC was used as secondary treatment. [92] There was no evidence of persistent systemic toxic effect. [93] Ocular complications included temporary eyelid edema, blepharoptosis, and orbital congestion with temporary dysmotility, as well as potentially blinding vascular obstruction. [93]
Recently, Kivelδ et al reported their initial experience with intravitreal methotrexate monotherapy in controling intraocular relapse of RB after chemoreduction. [94] Out of six eyes, two eyes that obtained complete response remained in remission at 22-40 months. However, as the authors mentioned, future prospective trials are warranted before making any conclusion of the activity of intravitreal methotrexate monotherapy on the basis of this preliminary data. Patel et al reported a case of unilateral RB that had failed prior IAC, and intra-arterial digoxin therapy produced a modest but measurable response. [95]
Shields et al have reported the regression patterns in an analysis of 557 RBs. [96] Following chemoreduction, large RB tends to regress to calcified remnant (type 1), medium RB to partially calcified remnant (type 3), and small RB to noncalcified remnant (type 2) or atrophic scar (type 4).
Children with hereditary RB have a high risk of second primary tumors (SPTs), more if treated with EBRT. [97],[98] A study from the Dutch retinoblastoma registry reported a cumulative incidence of any second malignancy to be 28.0% for patients with hereditary disease, after 40 years of follow-up. [97] Woo et al studied the association between age at onset and type of SPT. [99] They found that the median age at which SPTs occurred inside the radiation field was younger than that for SPTs occurring outside the radiation field or in patients who did not undergo irradiation. Sarcomas occurred more commonly inside the radiation field.
Enucleation is reserved for eyes with extensive RB, in which there is no hope for useful vision. It is established that postenucleation, high-risk pathological risk factors (PRFs) for metastasis and extraocular relapse include choroidal invasion, retrolaminar optic nerve invasion, scleral, and orbital invasion. [100] In an analysis of 387 globes enucleated with RB, Eagle found 55 (18%) had high-risk features including retrolaminar optic nerve invasion in 31 (10%) and massive uveal invasion of more than 3 mm in 24 (8%). [100] Chantada et al reported very high overall survival for patients with unilateral RB in their series in which they divided the subjects into those with lower risk PRFs and higher risk PRFs. [101] Group with lower risk PRFs included intraretinal, prelaminar optic nerve, any degree of choroidal invasion, and postlaminar optic nerve disease without concomitant full choroidal or scleral invasion. These patients did not receive any adjuvant therapy after enucleation. Group with higher risk PRFs included postlaminar optic nerve invasion with concomitant full choroidal or scleral invasion, tumor at the resection margin of the optic nerve, any degree of scleral invasion, postlaminar optic nerve invasion without concomitant full choroidal or scleral invasion, but with tumor extending more than 1 mm beyond the lamina cribrosa or involving more than 20% of the whole optic nerve stump. These patients received a total of eight cycles of adjuvant chemotherapy. Orbital radiotherapy, including the chiasm, was given within 2 weeks after enucleation for patients with tumor invasion to the resection line of the optic nerve only at a dose of 45 Gy. Shields et al reported treatment of patients with high-risk PRFs using vincristine, etoposide, and carboplatin for four to six cycles of additional chemotherapy. [102] However, there is still no universal agreement regarding the definition of "high risk" PRFs and the need for adjuvant therapy following enucleation. [103] Moreover, the use of chemoreduction for eye preservation in bilateral disease makes the interpretation of the impact of PRFs difficult. [104] COG has just finished a trial of unilateral RB with/without high-risk PRFs and the role of adjuvant chemotherapy in high-risk cases. [105] The results of this multicentre trial should help make guidelines for managing cases with high-risk PRFs.
RB is one disease where we have had significant advances in the last decade. As we learn more, we treat our children better.
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