Retinoblastoma

Retinoblastomas are the most common intraocular neoplasm found in childhood and with modern treatment modalities, are, in most cases, curable.

On imaging, they are generally characterized by a heterogeneous retinal mass with calcifications, necrotic components and increased vascularization on Doppler ultrasound/enhancement on CT/MRI. 

Epidemiology

Retinoblastomas may be sporadic or secondary to a germline mutation of the retinoblastoma protein tumor suppressor gene (RB), which is usually inherited. It may be unilateral or bilateral:

• bilateral (30-40% of cases) essentially always have a germline mutation ^5,6

• unilateral tumors (60-70% of cases) are caused by a germline mutation in approximately 15% of cases, whereas 85% are sporadic ^5,6

Thus, ~55% of cases are due to a germline mutation. This mutation is inherited in an autosomal dominant fashion with ~90% penetrance (i.e. the child of a retinoblastoma survivor who has a germline mutation has a 50% chance of inheriting a mutation, and if they do so a 90% chance of developing retinoblastoma. They thus have an overall probability of 45% of having a retinoblastoma (50% × 90%).

Most cases are diagnosed within the first four years of life, with a median age of diagnosis of 18-24 months ^5,6.

Children with germline mutations are also at increased risk of developing trilateral retinoblastoma (unilateral or bilateral retinoblastomas and pineoblastoma) ¹¹, quadrilateral retinoblastoma (trilateral retinoblastoma and suprasellar CNS embryonal tumor) ¹⁴ and osteosarcoma ^2,3 and usually present early (median age of diagnosis 12 months) ⁶.

Clinical presentation

Presentation is most frequently with leukocoria or loss of red-eye reflex, strabismus and decreased vision ¹⁵. Overall approximately 30-40% are bilateral and often synchronous. The bilateral occurrence is even higher in inherited forms and tends to occur at a younger age ^5,6.

Pathology

Three patterns of growth are recognized ^4,5:

1. endophytic

   • growth occurs inwards into the vitreous

   • cell clusters may detach and float in the vitreous (vitreous seeding)

2. exophytic

   • growth occurs outwards

   • associated with non-rhegmatogenous retinal detachment

3. combined endophytic and exophytic

Retinoblastoma may metastasize via direct spread into the orbit, along the optic nerve into the brain, or the subarachnoid space resulting in leptomeningeal metastases. It can also hematogenously metastasize preferentially to the bone, bone marrow and liver. Rarely, it will spread to regional lymph nodes ⁹.

Macroscopic appearance

Macroscopic and funduscopic examination reveals a white elevated mass with fine surface vessels ⁴.

Microscopic appearance

Histology demonstrates a small round-cell tumor of neuroepithelial origin. Flexner-Wintersteiner rosettes (relatively specific for retinoblastoma) and Homer-Wright pseudorosettes (also found in other PNETs) may be seen on microscopy.

Radiographic features

Ultrasound

Orbital sonography can be performed without sedation and can be repeated multiple times without exposing the child to ionizing radiation. Retinoblastomas appear as echogenic soft-tissue masses with variable shadowing due to calcifications and heterogeneity due to necrosis and hemorrhage ⁵. At diagnosis, tumors are usually vascular on Doppler examination.

The vitreous may have multiple areas of "floating" debris, which may represent vitreous seeding or alternatively, necrotic debris, hemorrhage or increased globulin content ⁵.

CT

It must be emphasized that CT scan is not recommended in the study of children with suspected or known retinoblastoma ¹². Therefore, MRI must be always preferred, because CT scan use may result in an increased risk of secondary malignancies related to radiation exposure. Moreover, high doses of radiation are especially harmful to this group of patients with heritable and germline retinoblastoma ¹³.

However, when a CT study is performed for any other indication, it may demonstrate a contrast-enhancing retrolental mass that is usually calcified. A dense vitreous due to hemorrhage is also common.

MRI

MRI is the modality of choice for pre-treatment staging on retinoblastoma (see retinoblastoma staging) ⁴.

MRI is often used in searching for optic nerve involvement, extraocular extension, and the possibility of a concomitant primitive neuroectodermal tumor (trilateral retinoblastoma with pineoblastoma). 

• T1: intermediate signal intensity, hyperintense compared to the vitreous ^4,5

• T2: hypointense compared to the vitreous

• T1 C+ (Gd)

  • the mass usually enhances relatively homogeneously when small

  • larger tumors often have areas of necrosis, rendering them heterogeneous

  • linear enhancement of the choroid beyond the margins of the tumor should raise the possibility of choroidal involvement, although inflammation may lead to a similar appearance ⁴

  • enhancement of the anterior chamber need not represent tumor involvement, with hyperemia, uveitis, and iris neovascularization all leading to asymmetric enhancement ⁴

  • careful assessment of the optic disc and optic nerve should be carried out to assess for involvement

  • extra-ocular extension through the sclera will be visible as an interruption of the otherwise hypointense non-enhancing sclera by enhancing tumor

• DWI/ADC

  • the tumor shows restricted diffusion on DWI at high b values. It exhibits low ADC values in contrast to the high intensity of the vitreous in the ADC maps

  • ADC map can be used to differentiate viable and necrotic tumor ⁷

  • DWI is valuable in evaluating the response to eye-preservation treatment ⁷

Treatment and prognosis

Treatment depends on tumor size and the stage of disease (see retinoblastoma staging) and involves one or more modalities:

• conservative

  • external-beam radiation therapy

  • cryotherapy

  • laser photocoagulation

  • radioactive plaque therapy

  • thermochemotherapy

  • tumor reduction chemotherapy

• surgical

  • enucleation

  • en bloc resection

Prognosis depends on the stage. Overall the cure rate has risen to over 90% in developed nations ⁴.

Patients with retinoblastoma rarely (<1%) go on to develop rhabdomyosarcoma, which itself perhaps arises due to chemotherapy, radiation therapy and/or an underlying genetic susceptibility ¹⁰.

Differential diagnosis

For imaging differentials consider:

• differential for calcification of the globe

• differential for an ocular mass

• differential for ocular enlargement