The retinoblastoma is a tumor of infancy and childhood and accounts for about 2 % of all malignant neoplasia in children. Experts recommend a simple screening test to diagnose retinoblastomas early: The frontal photography of an infant using flash reveals the most common symptom of the retinoblastoma – the leukocoria – and can be essential for an early diagnosis and an adequate therapy.


Retinoscan before and during chemotherapy

Picture: “Retinoscan before and during chemotherapy” by Morleyj. License: Public Domain


Definition of Retinoblastoma

Retinoblastoma – A malignant tumor of the retina

Retinoblastoma has the highest prevalence among intraocular tumors in children. It is a malignant tumor of the retina emanating from embryonic cells. The disease may affect one or both eyes and can appear sporadically or cumulated in families. Healing rate is almost at 100 % if the tumor is solely intraocular.

Epidemiology of Retinoblastoma

Retinoblastoma presents an incidence of 0,4 in 100.000. Main age of manifestation is the first year of one’s life. 80 % of diseased children are younger than 4 years. Girls and boys are affected equally often.

Pathogenesis of Retinoblastoma

Genetic causes of retinoblastoma

The two-hit-hypothesis of Knudson states that only a loss of both alleles of the retinoblastoma-gene is sufficient for the growth of a retinoblastoma. This gene is located on chromosome 13 and is involved in regulating the cell cycle. There are two types of retinoblastoma. First, there is the hereditary type, that amounts to 45 %, while the second type, the sporadic type, makes up 55 %. In the hereditary type, all somatic cells have lost one allele, so that the loss of a second allele in a retinal cell consequently induces the growth of a retinoblastoma. In 95 % of the cases, such secondary somatic mutation occurs, so that the inheritance is typically autosomal-dominant with incomplete, but very high penetration. Bilateral retinoblastomas are almost always hereditary.

If one of the parents is diseased with retinoblastoma, there is a 50 % chance for the offspring to inherit the mutated Rb-gene.

A multifocal appearance of the retinoblastoma is possible. Characteristic is an invasion into the vitreous body and spreading along the optic nerve into the brain, so that a meningeosis develops. In addition to this, an expansion across the sclera into the eye socket and alongside the ciliary arteries is also possible. Metastasis occurs after invasion through the Bruch’s membrane into the highly vasculated choroid by a hematogenous spread into bones, bonemarrow and lymph nodes.

Hereditary type Sporadic type
early diagnosis, about 12 months old late diagnosis, about 23 months old
bi- and unilateral appearance unilateral appearance
first mutation occuring in germline two somatic mutations
50% risk that offspring is getting affected offspring is at same risk as the remaining population
increased risk of further malignant tumors like osteosarcomas no increased risk of further malignant tumors

Clinical Symptoms of Retinoblastoma

The most common symptom, which can be observed in 3 out of 4 children, is the leukocoria or amaurotic cat’s eye reflex. The white pupil is caused by the tumor infiltrating the vitreous body. The consequent loss of vision often remains unnoticed by parents. Other symptoms are strabismus and a reddened aching eye caused by the emerging glaucoma which is a result of the tumor growth. Increasing impairment of vision or even blindness are caused by the destruction and detachment of the retina or the infiltration of the macula. In rare cases, a unilateral mydriasis, a heterochromia iridium or a hyphema can be observed.

leucocoria

leucocoria

Retrolental fibrovascular membranes in course of retinopathy of prematurity, uveitis and toxoplasmosis must be taken into consideration in the differential diagnosis of leucocoria.

Large retinoblastoma, infiltrating a large part of the glass body and the lens

Image: “Large retinoblastoma, infiltrating a large part of the glass body and the lens.” by The Armed Forces Institute of Pathology (AFIP). License: Public Domain

Diagnosis of Retinoblastoma

Versatile examinations for complete diagnostics of a retinoblastoma

Medical diagnosis is made with the help of examining the ocular fundus. A retinal tumor can be observed, which often has calcium depositions and causes retinal detachment. Also, the infiltration of the vitreous body or the anterior chamber can be visualized clearly by using indirect ophthalmoscopy. Staging and planning of therapies is made on the basis of a spinal tap and a bone marrow examination. In CT- and MRT-scans, the intraocular expansion can be evaluated. If a skeletal metastasis is suspected, a scintigraphy using Technetium 99 m may be required.

Fundus with retinoblastoma

Image: “Fundus with retinoblastoma” vby Filip em. License: CC BY 2.0

Note: A biopsy of the retinoblastoma is not indicated since tumor cells could be dispersed and carried over to adjacent structures of the eye bulb.

Staging using the Reese-Ellsworth classification

  • Infiltration of the optic nerve

    Image: “Infiltration of the optic nerve” by Openi. License: CC BY 2.0

    I: Tumor diameter of less than 4 mm.

  • II: Tumor diameter of 4 – 10 mm.
  • III: Tumor diameter of more than 10 mm or anterior to equator.
  • IV: multiple tumors with a disc diameter larger than 10mm or lesion extending anteriorly to the ora serrata.
  • V: Tumor involving more than half of the retina or vitreous seeding.

Therapy of Retinoblastoma

Characteristics of the retinoblastoma are essential

Conservative treatment, thus a bulb preservative treatment, is only indicated if it is possible to obtain a certain degree of vision. Among these treatments are photocoagulation, cryotherapy and external beam radiotherapy, since the tumor is very sensitive to radiation. Check-ups on a regular basis are crucial, since osteosarcoma may form in the field of radiation or a radiogenic cataract may develop. Clearly more elegant is the brachytherapy using episcleral plaque-radiation. For this an applicator containing Ruthenium-106 is patched onto the sclera and removed after the cumulative dose has been applied. An adjuvant chemotherapy is indicated when the tumor has metastasized.

Retinoscan before and during chemotherapy

Image: “Retinoscan before and during chemotherapy” by Morleyj. License: Public Domain

Enucleation of the eye is a valid option in patients with unilateral disease. Patients with bilateral retinoblastomas would keep the less affected eye and be treated conservatively whereas the opposite eye would be enucleated.

Special Types of Retinoblastoma

Trilateral retinoblastoma

MRT of trilateral retinoblastoma

Image: “MRT of trilateral retinoblastoma” by I. Aerts/L. Lumbroso-Le Rouic/M. Gauthier-Villars/H. Brisse/F. Doz und L. Desjardins. License: CC BY 2.0

The trilateral retinoblastoma is very uncommon. It is a hereditary retinoblastoma combined with a brain tumor. However, the brain tumor is no metastasis, but the histological findings are similar to the retinoblastoma. Altogether, the trilateral retinoblastoma faces poor prognosis.

Retinoma

The retinoma, also called retinocytoma, is a benign retinal tumor, which affects about 2 % of children having the retinoblastoma gene mutation. Assumptions say that retinoma is a precursor of the retinoblastoma or that it is a retinoblastoma after spontaneous regression, since histology is quite alike.

Prognosis of Retinoblastoma

Good chances for retinoblastoma patients

The 5-year survival rate amounts to 97 %. Prognosis is worse if the choroid or the optic nerve is infiltrated beyond resection border or if a bilateral affection is on hand. Findings of distant metastases require high-dose chemotherapy combined with a reinfusion of stem cells, which is the sole curative approach for therapy and comes along with a clearly worse prognosis.

Note: Long-term survival of patients having the hereditary type of retinoblastoma is determined by the higher rate of secondary malignant tumors.

Follow-Up Treatment of Retinoblastoma

If one parent has had a bilateral or a multifocal retinoblastoma, the patient generally is considered as a carrier of a constitutional mutation, which is inherited autosomal dominant. If an inheritance of the RB1-mutation cannot be ruled out by a molecular genetic test, the ocular fundus of the newborn child has to be examined under anesthetic within the first two weeks of its life. Furthermore, frequent examination of the ocular fundus should be performed by a pediatric ophthalmologist until the age of 3.

Descendants or brothers or sister of patients, having a sporadic type unilateral retinoblastoma, do not have higher disease risks. However, it has to be ruled out that it has been a unilateral retinoblastoma caused by germline mutations.

Due to the increased risk of secondary tumors after radiotherapy and especially in cases with constitutional heterozygosity, a life-long oncologic and ophthalmologic follow-up treatment of the affected patients is crucial.

Review Questions

The correct answers can be found below the references.

1. Which part of the body/organ is often affected by metastases of the retinoblastoma?

  1. Lung
  2. Liver
  3. Bone marrow
  4. Brain
  5. Skin

2. A 13-month old healthy boy is presented to you by his parents because his left eye had been reddened and aching for 2 weeks. The parents have already taken him to a pediatrician a week ago. His tentative diagnosis was a viral conjunctivitis and he was prescribed an eye ointment, which, however, did not alleviate symptoms. Now especially the child’s father is worried, since he read on the internet that such inflammation of the eye could indicate a tumor and he himself has also been wearing a glass eye ever since because he has had a tumor affecting his eye when he was young. How high are the chances that the boy is affected by a retinoblastoma if the father indeed has had a hereditary type retinoblastoma?

  1. Almost 100 percent
  2. Almost 50 percent
  3. 25 percent
  4. Same chance as the remaining population
  5. Approximately 0 percent, since children with retinaoblastoma do not reach propagable age and, therefore, the father cannot have had retinoblastoma.

3. How is stage V of the Reese-Ellsworth classifcation of the retinoblastoma defined?

  1. Tumor with a diameter of more than 10 mm or in front of the equator.
  2. Multiple tumors with a discus diameter greater than 10 mm or rostral to the ora serrata.
  3. The tumor takes one or vitreous sowing over half of the retina.
  4. The tumor occupies more than 3/4 of the retina or has formed distant metastases.
  5. Bilateral retinoblastoma
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