Case Study: Cross-Eyed
|Presenter: Debarshi Mustafi, MD, PhD
||Discussant: Jonathan Kim, MD
- Parents of a four-month-old male noted his right eye turning in and being “lazy”
- Patient born at 37 weeks gestation by normal vaginal delivery. He was discharged home postnatally without any complications.
- No significant past ocular history from either side of the family
- Evaluated by pediatrician who noted his right pupil was different than his left pupil
- Referred to an ophthalmologist and noted to have absent red reflex in the right eye and then transferred to Children’s Hospital Los Angeles for further work up of leukocoria
- Leukocoria can result from a variety of pathological processes that obstruct the natural path of light to the choroid to elicit the red reflex
- Coats disease
- Retinal hamartoma
- Persistent fetal vasculature
- Retinopathy of prematurity
- Toxocariasis (larval granuloma)
- Posterior cataract
- Organizing vitreous hemorrhage
- Congenital retinal fold
- Exam under anesthesia was carried out
- MRI brain and orbits did not reveal any signal abnormality or enhancement within the optic nerves.
- Bilateral retinoblastoma
- Although 10 percent of patients have a family history, the large majority of 90 percent are sporadic cases, as in this patient
- Does not rely on histopathological diagnosis as biopsy incurs the risk of metastasis
- Intraocular retinoblastoma was staged using the International Classification:
- The right eye in this patient was classified as Group D
- The left eye in this patient was classified as Group B
- Retinoblastoma can be traced to the RB1gene, a cell cycle regulator that binds to E2F transcription factors and represses genes related to cell proliferation
- Retinoblastoma can be divided into various subgroups
- Those with bilateral retinoblastoma (those with germinal mutations, and thus with risk of passing it on to their offspring)
- Those with unilateral retinoblastoma encompassing germinal and somatic mutations
- Biallelic RB1 inactivation is necessary to initiate most retinoblastomas, but it is not sufficient
- Benign retinal lesions such as a retinoma can involve loss of both RB1 alleles
- Further genetic or epigenetic changes, which are still poorly understood, are needed for malignant transformation
- A small subset of unilateral tumors shows no evidence of RB1 mutation, and instead has high-level amplification of the proto-oncogene MYCN
- Recent evidence suggests that the cell of origin for retinoblastoma may be the cone photoreceptor cell
- Enucleation is first line therapy for the majority of eyes with retinoblastoma globally, but is no longer the only choice as other options have emerged:
- IV chemotherapy with carboplatin, etoposide and vincristine (CEV) followed by focal consolidation
- Intra-arterial chemotherapy where chemo is delivered to ophthalmic artery of the eye with retinoblastoma
- Intravitreal chemotherapy to better treat vitreous seeds once source of seeds is controlled
- In this case, with one group B eye and one group D eye, the choice was made to proceed with six cycles of IV chemotherapy (CEV) with focal consolidation.
Prognosis and Future Directions
- The left eye still had three distinct tumors, without any growth or new tumors after initiation of CEV treatment.
- The patient will be followed up in four weeks with another exam under anesthesia.
- Even after tumor control, retinoblastoma patients require long-term follow up since they are predisposed to secondary sarcomas, especially osteosarcomas.
- The emerging options of intra-arterial and intravitreal chemotherapy have increased efficacy in treating later stage (groups C and D) retinoblastoma eyes and offer promise as an eye salvage option
- Increased understanding of the retinoblastoma molecular pathways and the underlying genetic signatures can lead to novel targeted therapies in the future.
- Current Treatment Options for Intraocular Retinoblastoma in 2017:
- Systemic Chemoreduction
- Transpupillary thermotherapy (Laser)
- Intra-arterial selective chemotherapy
- Intravitreal chemotherapy injection
- External Beam Radiation
- Primary therapy in 2017 for Groups B-D:
- Chemoreduction + Intravitreal chemotherapy
- Chemoreduction + Intravitreal chemotherapy
- Intra-arterial chemotherapy + Intravitreal chemotherapy
- Systemic chemoreduction: success rates for globe salvage
- Group B – 85 to 100 percent
- Group C – 75 to 90 percent
- Group D – 47 percent (82 percent with IMRT)
- Group E – 15 to 20 percent
- Intra-arterial chemotherapy (IAC)2006-7: Abramson et al. Ophthalmology 2008
- MSKCC Results in Group D eyes (MSKCC 2015) – 79% avoided enucleation or radiation
- Shields 2016:
- Unilateral Group D – 91% salvage rate (48% with chemoreduction)
- Yousef et al (Review of 12 IAC series through Jan 2015):
- Globe salvage rate – 66% overall, 57% for Group D/E
- Intravitreal chemotherapy using Melphalan (IVC): Munier Protocol 2012
- Mark the injection site 3.25 – 3.5mm posterior the limbus
- Paracentesis (0.1cc of aqueous humor)
- An injection is done with a 32 G needle in a quadrant of the eye free of tumor
- The needle is visualized behind the lens
- Cryotherapy is applied as the needle is withdrawn
- The eye is then shaken to distribute the chemotherapy
- Overview of clinical results in published series of IVC: control rate of vitreous seeds 68 – 100 percent
- Munier 2012
- 23 eyes, 122 injections, 20 – 30 ug
- Weekly injections, total of 3 – 7 per eye (average 4.5)
- 87% globe salvage, median follow-up duration of 13.5 months
- Abramson 2014 – 15
- 107 eyes: 30 ug, median 6.5 injections per eye, salvage 90%
- Decreased ERG responses at 30ug (5.8 uV per injection)
- Shields 2012 – 16
- 12 eyes, 8 – 50 ug, 60% salvage rate (> six months follow-up)
- 40 eyes, 20 – 30 ug, 100%, globe salvage 88% (Three years follow-up)
- Suzuki et al, 2015
- 8 – 16 ug, 264 eyes, vitreous seed control 68%, 124 months follow-up
- Current treatment options for RB: Summary
- Unilateral Group E, Unilateral Group D with poor visual potential
- Systemic Chemotherapy
- Bilateral cases (Groups B – D). Unilateral Group B – D.
- Groups B – D < six months of age
- Intra-arterial chemotheraphy
- Unilateral Group D (> six months), Groups B and C
- Salvage of retinal tumors after chemoreduction
- Intravitreal melphalan
- Salvage of vitreous seeding
- Peripheral Group B and C tumors
- External beam radiation
- Last modality before enucleation of second eye
- Bilateral salvage of retinal recurrences after IAC, order than 12 months of age
- Dimaras H, et al.Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum. Mol. Genet. 2008 May 15;17(10):1363-1372.
- Dryja TP, Rapaport JM, Joyce JM, Petersen RA. Molecular detection of deletions involving band q14 of chromosome 13 in retinoblastomas. Proc. Natl Acad Sci USA. 1986 Oct;83(19):7391-4.
- Friend SH, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986 Oct 16-22;323(6089):643-646.
- Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad Sci USA. 1971 Apr; 68(4):820-823.
- Munier FL, et al.Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br. J. Ophthalmol. 2012;96:1078-1083.
- Linn Murphree A. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am. 2005 Mar;18(1):41-53.
- Rushlow DE, et al.Characterisation of retinoblastoma without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol. 2013;14:327-334.
- Xu XL, et al.Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling. Cell. 2009 Jun 12;137(6):1018-1031.
Produced by: Monica Chavez, John Daniel, Joseph Yim and Dr. Vivek Patel