GENERALITIES

Retinoblastoma, as indicated in the name, is a tumor that arises from immature retinal cells. It is the most common primary intraocular tumor in children, accounting for 4% of all pediatric malignancies, with the mean age at clinical presentation being 2 years in unilateral forms and 1 year in bilateral forms.(1,2)

Retinoblastoma can be bilateral or unilateral. All the bilateral cases and 15% of unilateral retinoblastoma are due to a constitutional mutation of the RB-1 gene, which can be hereditary or de novo.(2)

It is a curable tumor if detected while still confined to the globe and if there are no metastatic risk factors, the child will nearly always survive following appropriate treatment.(3)

CLINICAL PRESENTATION

The two most frequently revealing symptoms of retinoblastoma are leukocoria and strabismus, but we can also observe others such as hypopyon, iris rubeosis, hyphema, buphthalmos, orbital cellulitis, and exophtalmia.(4)

IMAGING DIAGNOSIS

Diagnosis relies first on fundoscopy and ultrasound (US), then MRI for further assessment and mostly pre-operative strategy.

The purpose of imaging is to determine laterality, number, location, size of the tumor, local extent (endophytic growth in the vitreous chamber, exophytic growth in the subretinal space, or infiltrative growth along the retina), regional extent: intracranial tumor invasion, association with primitive neuroectodermal tumor (PNET), brain malformations.

- Ultrasound, with a high-frequency probe:

Fig 1: A. Guidelines for imaging retinoblastoma: imaging principles and MRI standardization B. Guide for Providing Essential Insights for Ophthalmologists and Oncologists. Radiographic

Irregular mass, more echogenic than the vitreous, with fine calcifications.

Retinal detachment may also be observed in exophytic forms and is an important feature in defining tumor growth patterns, either endophytic or exophytic, or a combination of both.

Calcifications are present in almost 95% of retinoblastomas and can be a key to differentiating it from other mass lesions in young children.

To report: the presence of a mass, its location, size, calcification, vascularization on color doppler, and retinal detachment.

- Computed Tomography CT

Fig 6: Non enhanced CT scan in a 5 year old boy prensenting chronic headache. Right intraocular posterior solid mass with calcifications, in favor of a retinoblastoma.

Retinoblastoma manifests typically as a high-density mass compared to the vitreous body, moderately enhancing after iodinated contrast administration. The main characteristic to note in this imaging modality is the presence of calcifications, with a sensitivity of 81-96% and an even higher specificity.(2)

However, CT evaluation of detailed soft tissue invasion for retinoblastoma is limited.

- Magnetic resonance imaging MRI:

The Purpose of the MRI:

1. Positive diagnosis: 

The imaging modality of choice to assess the local extension is MRI. The mass has a signal equivalent to or slightly more intense than the vitreous on T1-weighted sequences, with a relatively low-intensity signal on T2-weighted sequences. Fine calcifications are not visible.

Increased spatial resolution will improve the accuracy of MRI in assessing the anatomical details of the papilla, lamina cribrosa, and pre and post laminar segments of the optic nerve (ON) (the image plan should align with the orientation of the distal end of the nerve, just posterior to the lamina cribrosa) (5)

Fig 3: Overall anatomical description of the globe and segments of the optic nerve. Sagittal MR image T2-Weighted

2. Extension: MRI can depict extension to the ON, anterior chamber, and orbital fat. The systematic brain sequences associated can depict extra-orbital extension to the brain.
3. Differential diagnosis: pseudo tumoral conditions such as coats disease or eye malformations and diagnosing rare cases of trilateral retinoblastoma

The differential diagnosis is mostly suspected when confronted with a diffuse, invasive form of retinoblastoma, usually without calcifications (5).

MRI Protocol: Although every MRI should be tailored to the individual's specific queries, a protocol consensus has been reached among members of the European Retinoblastoma Imaging Collaboration (ERIC)

Fig 2: MRI protocol for Retinoblastoma evaluation and diagnosis.

TIPS for assessing retinoblastoma – MRI check list:

1. Tumor

• Is the tumor unilateral or bilateral?
  

  Fig 11: Retinoblastoma in a 10 month old boy revealed by a bilateral leukocoria. a.T2 coronal b.T1 coronal c.T1 coronal Dixon Water with gadolinium d. T1 Axial Dixon Water with gadolinium. MRI show a bilateral posterior solid intraocular mass in low T2 intensity, and slightly high T1 intensity, enhanced after gadolinium injection.
  

  Fig 10: Leukocoria in a 17-month-old girl. Axial MRI images (a. FLAIR, b.T2-W, c.T1-W + gadolinium), and coronal MRI images (d.T2, e.T1 DIXON water, f.T1+ gadolinium) showing a right intra-ocular solid mass (white arrow) in the nasal visual field hypointense in T2 weighted images, hyperintense in T1 weighted images, enhanced after gadolinium injection. Note that the masse comes in contact with the right medial rectus, and show no contact with the lens. There was also a slight enlargement of the intraocular portion of the optic nerve without evident enhancement.
• Determine tumor size
• The location: anterior or posterior or combined concerning the equator of the eye
• It should be mentioned if the tumor is close to the optic disc.
• Does the tumor present an endophytic or exophytic growth pattern?
  

  Fig 4: - Deformation of the globe: axial enhanced T1-W shows infiltrative retinoblastoma responsible for a globe deformation. - Reduced anterior chamber depth: axial T2-W. - Endophytic growth: Axial T2-W. - Vitreous seeding: Axial 3D fast spin-echo MR images show three 1–2-mm vitreous seeds (arrows) in the eye.   © High-Resolution MR Imaging of the Orbit in Patients with Retinoblastoma - Retinal detachment   ©   High-Resolution MR Imaging of the Orbit in Patients with Retinoblastoma - Exophytic growth: Transaxial contrast-enhanced T1-W shows an exophytic retinoblastoma with secondary total retinal detachment and proteinacious subretinal effusion. © Guidelines for imaging retinoblastoma: imaging principles and MRI standardization
   
  • Endophytic growth pattern is associated with possible vitreous seeding
  • Exophytic growth pattern is associated with more frequent retinal detachment, subretinal seeding, and choroid invasion.(5)
• Is it associated with retinal detachment?
  

  Fig 4: - Deformation of the globe: axial enhanced T1-W shows infiltrative retinoblastoma responsible for a globe deformation. - Reduced anterior chamber depth: axial T2-W. - Endophytic growth: Axial T2-W. - Vitreous seeding: Axial 3D fast spin-echo MR images show three 1–2-mm vitreous seeds (arrows) in the eye.   © High-Resolution MR Imaging of the Orbit in Patients with Retinoblastoma - Retinal detachment   ©   High-Resolution MR Imaging of the Orbit in Patients with Retinoblastoma - Exophytic growth: Transaxial contrast-enhanced T1-W shows an exophytic retinoblastoma with secondary total retinal detachment and proteinacious subretinal effusion. © Guidelines for imaging retinoblastoma: imaging principles and MRI standardization
   
• Signs of increased intraocular pressure: globe deformation, and reduced anterior chamber depth
  

  Fig 4: - Deformation of the globe: axial enhanced T1-W shows infiltrative retinoblastoma responsible for a globe deformation. - Reduced anterior chamber depth: axial T2-W. - Endophytic growth: Axial T2-W. - Vitreous seeding: Axial 3D fast spin-echo MR images show three 1–2-mm vitreous seeds (arrows) in the eye.   © High-Resolution MR Imaging of the Orbit in Patients with Retinoblastoma - Retinal detachment   ©   High-Resolution MR Imaging of the Orbit in Patients with Retinoblastoma - Exophytic growth: Transaxial contrast-enhanced T1-W shows an exophytic retinoblastoma with secondary total retinal detachment and proteinacious subretinal effusion. © Guidelines for imaging retinoblastoma: imaging principles and MRI standardization

2. Optic nerve and meningeal sheath invasion
   

   Fig 5: -- Choroid invasion: Axial contrast-enhanced fat-saturated T1-weighted MR image shows a heterogeneously enhancing retinoblastoma (solid arrow). Note the thickening and discontinuity of the normal curvilinear choroidal enhancement (dotted arrow) suggestive of choroidal invasion. (6) -- Lens invasion: Axial T2-W showing a nodular lesion in the lens showing the same characteristics as the retinoblastoma. -- Ciliary body invasion: enhanced axial T1-W shows an exaggerated enhancement of the ciliary body suggesting local invasion. -- Post-laminar ON invasion: axial T1-W shows a post-laminar ON enhancement. (6) -- Scleral invasion: axial enhanced T1-W irregularity of the sclera suggestive of scleral invasion.

• The direct radiological criterion used to diagnose post laminar nerve invasion is the presence of abnormal contrast enhancement (enhancement ≥ 2 mm in diameter) in the distal nerve.(6)
• Interruption of normal linear enhancement at the optic nerve disk (choroidoretinal complex) suggests an optic nerve invasion.
• Beware that increased intraocular pressure might have a posterior bulging of the lamina cribrosa, simulating post laminar ON invasion.

3. Ocular wall invasion and extraocular extension
   

   Fig 7: Retinoblastoma in a 2 years-old boy with a history of enucleation of the left eye due to a retinoblastoma. A 1,5 Tesla MRI, a. Axial T2-weighted, b. axial T1-weighted, c. Coronal T1-Weighted, d. enhanced T1-Weighted. The images show a posterior, irregular, intraocular mass hypointense in T2-W, and slightly hyperintense in T1-W images (white arrow). The mass presents an endophytic and exophytic growth with scleral invasion and retinal detachment. Note the choroidal thickening (dashed arrow) with enhancement of the adjacent intra-conic fat. There was also an ON and meningeal enhancement compatible with invasion of these structures (not shown clearly in these images)

• Is the choroid invaded?
  

  Fig 5: -- Choroid invasion: Axial contrast-enhanced fat-saturated T1-weighted MR image shows a heterogeneously enhancing retinoblastoma (solid arrow). Note the thickening and discontinuity of the normal curvilinear choroidal enhancement (dotted arrow) suggestive of choroidal invasion. (6) -- Lens invasion: Axial T2-W showing a nodular lesion in the lens showing the same characteristics as the retinoblastoma. -- Ciliary body invasion: enhanced axial T1-W shows an exaggerated enhancement of the ciliary body suggesting local invasion. -- Post-laminar ON invasion: axial T1-W shows a post-laminar ON enhancement. (6) -- Scleral invasion: axial enhanced T1-W irregularity of the sclera suggestive of scleral invasion.
   
  • The choroid has dense vasculature, its invasion is associated with increased risk of metastasis.
  • The choroid is a thin avidly enhancing layer just beneath the non-enhancing sclera.
  • Discontinuity and thickening of the normal curvilinear choroid may be an imaging marker of choroid invasion. (6)
• Is there a scleral invasion?
  

  Fig 5: -- Choroid invasion: Axial contrast-enhanced fat-saturated T1-weighted MR image shows a heterogeneously enhancing retinoblastoma (solid arrow). Note the thickening and discontinuity of the normal curvilinear choroidal enhancement (dotted arrow) suggestive of choroidal invasion. (6) -- Lens invasion: Axial T2-W showing a nodular lesion in the lens showing the same characteristics as the retinoblastoma. -- Ciliary body invasion: enhanced axial T1-W shows an exaggerated enhancement of the ciliary body suggesting local invasion. -- Post-laminar ON invasion: axial T1-W shows a post-laminar ON enhancement. (6) -- Scleral invasion: axial enhanced T1-W irregularity of the sclera suggestive of scleral invasion.
  

  Fig 9: MRI of a 3years-old girl. (a) Axial T1-Dixon Water (b) Axial T2 Dixon Water (c) Axial enhanced T1 Dixon Water, (d) sagittal enhanced T1 Dixon Water. Right eye retinoblastoma (arrow) enhanced after gadolinium administration, with scleral enhancement in favor of invasion (dotted arrow)
  • Scleral invasion is identified when tumor enhancement extends across the choroid interrupting the non-enhancing sclera.
  • It’s suspected when tumor enhancement extends into periocular tissues.(6)

4. Anterior eye segment 

• Is there an invasion of the anterior segment?
  

  Fig 5: -- Choroid invasion: Axial contrast-enhanced fat-saturated T1-weighted MR image shows a heterogeneously enhancing retinoblastoma (solid arrow). Note the thickening and discontinuity of the normal curvilinear choroidal enhancement (dotted arrow) suggestive of choroidal invasion. (6) -- Lens invasion: Axial T2-W showing a nodular lesion in the lens showing the same characteristics as the retinoblastoma. -- Ciliary body invasion: enhanced axial T1-W shows an exaggerated enhancement of the ciliary body suggesting local invasion. -- Post-laminar ON invasion: axial T1-W shows a post-laminar ON enhancement. (6) -- Scleral invasion: axial enhanced T1-W irregularity of the sclera suggestive of scleral invasion.
  

  Fig 8: 7 year old boy with left eye retinoblastoma. 1,5 Tesla MRI in axial T2-weighted (a), T1-weighted (b), enhanced T1-Weighted (c), and coronal T2-weighted (b). Images show a retinal detachment with an irregular retinal thickening hypointense in T2-W, slightly hyperintense in T1-W images with calcifications, and enhancement after gadolinium administration. Note the mass in the left lens shows the same characteristics as the one in the retinal detachment, compatible with retinoblastoma with lens invasion.
  • Anterior segment invasion indicates involvement of the ciliary body, lens, iris, and/or cornea.
  • Enhancement of the ciliary body or beyond, contiguous with the tumor, should raise suspicion for anterior segment invasion.(2)
  • It’s a high risk of hematogenous spread, warranting enucleation.

5. Brain

• Midline embryonal tumors: pineal, sellar or suprasellar mass associated
• Trilateral retinoblastoma refers to the occurrence of bilateral ocular RBs and primitive midline neuroectodermal tumor arising in the pineal region or the suprasellar cistern
• Leptomeningeal metastases.

DIFFERENTIAL DIAGNOSIS

• • • Coats disease: also known as retinal telangiectasis, is characterized by retinal telangiectasia and retinal exudation. It often manifests with leukocoria. The absence of calcification and enhancement at gadolinium-based contrast-enhanced MR imaging are indicative of Coats disease.
    • Persistent fetal vasculature = Persistent hyperplastic primary vitreous results from improper development of the embryonic primary vitreous. The persistence and proliferation of primary vitreous leads to development of fibrovascular tissue posterior to the lens and along the hyaloid canal.
    • Coloboma of Choroid: congenital defect in which the choroidal fissure fails to close, leading to a gap in the choroidal layer of the globe. This disease may be the cause of clinical manifestation of leukocoria. Diagnosing coloboma is usually easy at retinoscopy, and may be seen as scleral bulge at T2-Weighted MR imaging.
    • Retinal astrocytic Hamartoma: benign malformation that resembles focal disorganized tissue elements in the organ of origin, arising from the nerve fiber layer of the retina. Its generally associated with tuberous sclerosis, or even neurofibromatosis.

POST-TREATMENT AND FOLLOW-UP

The treatment depends on tumor volume, position, intraocular and extraocular extension, laterality.

MRI plays an important role in monitoring focal response to therapy and the potential extension of the tumor, either in terms of increased size or extension to the adjacent structures.

The evaluation should also monitor the focal response to therapy and the development of recurrent tumors, but also second primary malignancy in association to the radiation treatment or as an independent process.(7)