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LARGEST STUDY ON CHINESE AMERICANS PUBLISHED

LARGEST STUDY ON CHINESE
AMERICANS PUBLISHED

USC Ophthalmology Researchers Find More
Effective Treatments For Blinding Eye Diseases

EDUCATION

Case Study: Cross-Eyed

Mustafi Kim
Presenter: Debarshi Mustafi, MD, PhD Discussant: Jonathan Kim, MD
 

History

  • 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

Exam Findings

  • 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

Differential Diagnosis

  • Leukocoria can result from a variety of pathological processes that obstruct the natural path of light to the choroid to elicit the red reflex
    • Retinoblastoma
    • Coats disease
    • Retinal hamartoma
    • Persistent fetal vasculature
    • Retinopathy of prematurity
    • Toxocariasis (larval granuloma)
    • Posterior cataract
    • Organizing vitreous hemorrhage
    • Congenital retinal fold

Additional Investigations

  • Exam under anesthesia was carried out
Figure 1
Figure 1: RetCam images of a large creamy white lesion filling the globe and preventing view of any normal anatomic structures of the right eye. A complete retinal detachment is noted with diffuse seeds evident in the vitreous.
Figure 2
Figure 2: A) RetCam image of the left eye revealed three distinct
tumors (black and white arrows). B) The large tumor adjacent to the optic nerve (white arrow) is further visualized by hand-held OCT imaging.
  • MRI brain and orbits did not reveal any signal abnormality or enhancement within the optic nerves.

Diagnosis

  • 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:

Cross-eye table

  • The right eye in this patient was classified as Group D
  • The left eye in this patient was classified as Group B

Pathophysiology

  • 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

Treatment

  • 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

Figure 3
Figure 3: RetCam image of the right eye after two cycles of CEV showing re-attachment of the retina and discernable structures such as the optic nerve. Diffuse vitreous seeds (black arrow), which are cells shed from retinoblastoma that remain viable in the vitreous and subretinal space, are clearly visible now.
  • 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:
    • Enucleation
    • Systemic Chemoreduction
    • Transpupillary thermotherapy (Laser)
    • Cryotherapy
    • Brachytherapy
    • 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
    • Enucleation
      • 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
    • Brachytherapy
      • 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

References

  • 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.

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