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Ocular System

Retinoblastoma

Rare cancer usually initiated by biallelic mutation of the retinoblastoma gene (RB1) in a single susceptible developing retinal cell.

Rare cancer usually initiated by biallelic mutation of the retinoblastoma gene (RB1) in a single susceptible developing retinal cell.

  • M/C primary malignant intraocular tumour of children (3% of all childhood tumours)
  • #2 M/C intraocular malignant tumour
  • M/C cause of intraocular calcification
  • D/t mutation of Rb gene located in chromosome 13q14
  • 1st cancer to be directly associated with a genetic abnormality

History:

Pawius described retinoblastoma as early as in 1597 referred to the tumor as fungus hematodes and suggested enucleation as the primary mode of management. The discovery of ophthalmoloscope in 1851 facilitated recognition of specific clinical features of retinoblastoma. Initially thought to be derived from the glial cells, it was called glioma retinae by Virchow (1864). Flexner (1891) and Wintersteiner (1897) believed it to be a neuroepithelioma because of the presence of rosettes. Later, there was a consensus that the tumor originated from the retinoblasts and the American Ophthalmological Society officially accepted the term retinoblastoma in 1926. Retinoblastoma was associated with near certain death just over a century ago. There has been a dramatic change in the overall management of retinoblastoma in the last decade. Specific genetic protocols have been able to make pre natal diagnosis of retinoblastoma. Early diagnosis and advancements in focal therapy have resulted in improved eye and vision salvage.


Epidemiology

Global retinoblastoma treatment centres and patient distribution relative to resources: One Retinoblastoma World (www.1rbw.org) shows Retinoblastoma Centres of Excellence, providing a resource for affected families to access expert care. The majority of patients reside in low and middle income countries, while the majority of Retinoblastoma Centres are in high income countries. | Images from www.1rbw.org.

Etiology

Genetics: Two hit hypothesis

In 1971, Knudson proposed the two hit hypothesis. He stated that for retinoblastoma to develop, two chromosomal mutations are needed. In hereditary retinoblastoma, the initial hit is a germinal mutation, which is inherited and is found in all the cells. The second hit develops in the somatic retinal cells leading to the development of retinoblastoma. Therefore, hereditary cases are predisposed to the development of monocular tumors such as osteosarcoma.
Genetic origins of retinoblastoma
Genetic origins of retinoblastoma: Three genetic subtypes of retinoblastoma are known. Heritable retinoblastoma patients have a constitutive inactivating mutation (M1) in the RB1tumor suppressor gene in all cells of their body. A second, somatic mutation (M2) in a susceptible retinal cell can lead to benign retinoma. Further genetic and/or epigenetic events (M3…Mn) are required to transform to retinoblastoma. Non-heritable, RB1−/− retinoblastomas progress similarly, except both M1 and M2 occur in one susceptible retinal cell. RB1+/+MYCN-amplified (RB1+/+MYCNA) retinoblastoma is a rare, non-heritable retinoblastoma subtype driven by amplification of MYCN with normal RB1; other changes in these tumours remain uncharacterized. Retinoma histology shows distinct photoreceptor-like fleurettes, whereas RB1−/− retinoblastoma can show Flexner-Wintersteiner (insert) and Homer Wright rosettes (not shown). RB1+/+MYCNA retinoblastoma have a distinct morphology with rounded nuclei and prominent nucleoli related to the high MYCN protein. | Dimaras, H., Corson, T. W., Cobrinik, D., White, A., Zhao, J., Munier, F. L., Abramson, D. H., Shields, C. L., Chantada, G. L., Njuguna, F., & Gallie, B. L. (2015). Retinoblastoma. Nature reviews. Disease primers, 1, 15021. https://doi.org/10.1038/nrdp.2015.21

In unilateral sporadic retinoblastoma, both the hits occur during the development of the retina and are somatic mutations. Therefore there is no risk of second monocular tumors.


Pathophysiology

Disease progression:

Progression of retinoblastoma
Progression of retinoblastoma: a) Anatomical features of a healthy eye. Genomic damage (orange lightning bolt) leads to mutation of RB1 resulting in biallelic functional loss of RB1 in a developing retinal cell (possibly a cone photoreceptor precursor cell that is dependent on pRB to stop proliferation). b) Genomic instability leads to a benign retinoma; only 5% of patients show retinoma without retinoblastoma. Inset shows a small retinoma/tumour not visible except by optical coherence tomography. c) Intraretinal retinoblastoma arises as additional genomic changes promote uncontrolled cell proliferation; the tumour grows and seeds become independent, floating under the retina and into vitreous. d) Retinoblastoma can invade adjacent tissues: into the optic nerve, uvea, or sclera to constitute high-risk pathologic features. e) Eventually, retinoblastoma can extend extraocularly into orbit and metastasize especially to the bone marrow, or into the brain (direct or via the cerebrospinal fluid). | Dimaras, H., Corson, T. W., Cobrinik, D., White, A., Zhao, J., Munier, F. L., Abramson, D. H., Shields, C. L., Chantada, G. L., Njuguna, F., & Gallie, B. L. (2015). Retinoblastoma. Nature reviews. Disease primers, 1, 15021. https://doi.org/10.1038/nrdp.2015.21

Growth patterns:

  • Endophytic tumor (tumor grows into the vitreous cavity)
    • Yellow white mass progressively fills entire vitreous cavity and vitreous seeds occur.
    • Retinal vessels not seen on tumor surface.
  • Exophytic tumor (tumor grows into vitreous cavity)
    • Retinal detachment usually occurs
    • Retinal vessels seen over tumor
  • Diffuse infiltrating tumour (tumor diffusely involves the retina causing just a placoid thickness of retina and not a mass)
    • Generally seen in older children and usually there is a delay in the diagnosis.

Atypical manifestations of retinoblastoma:

  • Pseudohypopyon
  • Spontaneous hyphema
  • Vitreous hemorrhage
  • Phthisis bulbi
  • Preseptal/orbital cellulitis

Presentation

Common features:

  • Leukocoria “cat’s eye reflex” (white pupil) (M/C clinical presentation)
  • Strabismus/squint (misaligned eyes) (#2 M/C clinical presentation)
Leukocoria
Leukocoria (white reflection in the pupil) | Aerts, I., Lumbroso-Le Rouic, L., Gauthier-Villars, M., Brisse, H., Doz, F., & Desjardins, L. (2006). Retinoblastoma. Orphanet journal of rare diseases, 1, 31. https://doi.org/10.1186/1750-1172-1-31

Advanced disease presentation:

  • Heterochromia iridis
  • Enlarged cornea and eye due to increased pressure
  • Non-infective orbital inflammation

Very late presentation:

  • Eyes bulging from orbit

International Classification of Intraocular Retinoblastoma (IIRC) classification:

Classifies eyes in groups A to E, with E being the most severe
Different classification schemes for intraocular retinoblastoma confound comparison of outcomes
Different classification schemes for intraocular retinoblastoma confound comparison of outcomes: The features listed determine the overall classification, ranging from small tumours not threatening vision (“Group A”) to tumours clinically noted to have features suggesting potential spread outside the eye (“Group E”). Most importantly, size of tumour alone does not make an eye dangerous by Murphree, Children’s Oncology Group (COG), or TNM classification; but any eye with tumour >50% of eye volume is E (advanced-stage disease) by Shields classification. The consequence is widespread confusion in the literature undermining clinical research, since studies using the different classifications cannot be compared. The red boxes indicate the critical differences between the different classifications. | Dimaras, H., Corson, T. W., Cobrinik, D., White, A., Zhao, J., Munier, F. L., Abramson, D. H., Shields, C. L., Chantada, G. L., Njuguna, F., & Gallie, B. L. (2015). Retinoblastoma. Nature reviews. Disease primers, 1, 15021. https://doi.org/10.1038/nrdp.2015.21

Diagnosis

Indirect ophthalmoscopy

With the pupil pharmacologically dilated
Ocular fundus aspect of retinoblastoma
Ocular fundus aspect of retinoblastoma: The lesion appears as a white tumor with angiomatous dilatation of the vessels | Aerts, I., Lumbroso-Le Rouic, L., Gauthier-Villars, M., Brisse, H., Doz, F., & Desjardins, L . (2006). Retinoblastoma. Orphanet journal of rare diseases, 1, 31. https://doi.org/10.1186/1750-1172-1-31

Ocular ultrasonography (B-scan)

  • Calcification (characteristic of retinoblastoma)
B-scan showing echogenic mass fiiling the vitreous cavity
B-scan showing echogenic mass fiiling the vitreous cavity- confirming diagnosis of retinoblastoma. | Pandey A. N. (2014). Retinoblastoma: An overview. Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society, 28(4), 310–315. https://doi.org/10.1016/j.sjopt.2013.11.001

MRI:

CT scans avoided because radiation induces second primary cancers in people carrying RB1 mutations
  • Assess invasion of the optic nerve
  • Presence of trilateral retinoblastoma (pinealoblastoma and primitive neuroectodermal intracranial tumours associated with RB1 mutations)
MRI pattern of retinoblastoma
MRI pattern of retinoblastoma with optic nerve involvement (sagittal enhanced T1-weighted sequence) | Aerts, I., Lumbroso-Le Rouic, L., Gauthier-Villars, M., Brisse, H., Doz, F., & Desjardins, L. (2006). Retinoblastoma. Orphanet journal of rare diseases, 1, 31. https://doi.org/10.1186/1750-1172-1-31

Differential diagnosis

Detailed retinal examination under general anaesthesia is required to distinguish the differential diagnoses
  • Coats’ disease
  • Persistent foetal vasculature
  • Vitreous hemorrhage

Pseudoglioma:

Heterogeneous group of diseases that may be confused clinically with retinoblastoma
  • Norrie disease
  • Toxocara infection
  • Persistent hyperplastic primary vitreous

Management

Mainstay treatment:

Intravenous chemotherapy (IVC)/intra-arterial chemotherapy (IAC) + focal therapy (laser therapy, cryotherapy)
  • VEC regimen: Vincristine, Etoposide, Carboplatin
  • Cryotherapy: Preferred for anterior lesions
  • Phototherapy: Preferred for posterior lesions
Primary treatment choices based on the Murphree IIRC
Primary treatment choices based on the Murphree IIRC: Treatment depends on the combined severity of each of the affected eyes (Eye 1 | Eye 2); the preferred option for each eye is depicted in the blue boxes. IIRC Group A eyes can be treated with only laser or cryotherapy (focal therapy consolidation). Group B and C eyes require several cycles of systemic intravenous chemotherapy (IVC) or intra-arterial chemotherapy (IAC) followed by focal therapy and intravitreal chemotherapy with melphalan and/or topotecan for residual or recurrent vitreous seeds. Isolated single tumours in Group B or C eyes may occasionally be appropriate for primary radioactive plaque therapy. Group D eyes require either IVC (with focal therapy consolidation) or IAC (with focal therapy consolidation). All eyes with features suggesting imminent extraocular extension (Group E) should be removed so that accurate pathological examination can be performed to determine risk of metastasis requiring adjuvant chemotherapy. | IIRC, International Intraocular Retinoblastoma Classification. | Dimaras, H., Corson, T. W., Cobrinik, D., White, A., Zhao, J., Munier, F. L., Abramson, D. H., Shields, C. L., Chantada, G. L., Njuguna, F., & Gallie, B. L. (2015). Retinoblastoma. Nature reviews. Disease primers, 1, 15021. https://doi.org/10.1038/nrdp.2015.21

Enucleation:

Performed when there is infiltration of the anterior chamber, neovascular glaucoma, invasion of the optic nerve, and if the tumor comprises more than half of the vitreous volume or due to chemotherapy failure

Reese-Ellsworth classification

Help determine the likelihood of preserving vision while still treating the tumor
Reese-Ellsworth Classification
Reese-Ellsworth Classification of Intraocular Retinoblastoma | Treatment of Retinoblastoma: The Role of External Beam Radiotherapy – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Reese-Ellsworth-Classification-of-Intraocular-Retinoblastoma_tbl1_283239979 [accessed 29 Sep, 2020]

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