Retinoblastoma (RB) — Inheritence, Staging and Special Types

Image : “Retinoblastoma” by unknown. 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 retinal tumor emanating from embryonic cells. The disease may affect one or both eyes and can appear sporadically or cumulatively in families. The healing rate is almost 100% if the tumor is solely intraocular.

Epidemiology of Retinoblastoma

The incidence of retinoblastoma is 0.4 cases in 100,000. The primary age of its manifestation is the first year of one’s life. 80% of diseased children are younger than 4 years. Girls and boys are equally affected.

Pathogenesis of Retinoblastoma

Genetic causes of retinoblastoma

The two-hit hypothesis of Knudson states that a loss of both alleles of the retinoblastoma gene (RB1) is required to trigger the development of retinoblastoma. This gene is located on chromosome 13 and is involved in regulating the cell cycle. There are 2 types of retinoblastoma. The first type is the hereditary type that accounts for 45% of cases, and the 2nd type, the sporadic type, accounts for the remaining 55%. In the hereditary type, all somatic cells have lost 1 allele. Therefore, the loss of a 2nd allele in a retinal cell induces the growth of retinoblastoma. In 95% of 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.

“Retinoblastoma: Molecular Pathology” Image created by Lecturio

If one of the parents had retinoblastoma, there is a 50% chance for the offspring to inherit the mutated RB1 gene.

Retinoblastoma may be multifocal. The disease is characterized by an invasion into the vitreous body, further spreading along the optic nerve into the brain, causing the development of meningitis. In addition to this, the disease may expand across the sclera into the eye socket and alongside the ciliary arteries. Metastasis occurs after invasion takes place through Bruch’s membrane into the highly vascular choroid through hematogenous, finally spreading into bones, bone marrow, and lymph nodes.

Clinical Symptoms of Retinoblastoma

The most common symptom, which can be observed in 3 out of 4 children, is leukocoria or amaurotic cat’s eye reflex. The tumor infiltrating the vitreous body causes the white pupil. The consequent loss of vision often remains unnoticed by parents. Other symptoms are strabismus and an aching reddened eye caused by emerging glaucoma due to the growth of the tumor. The destruction and detachment of the retina or the infiltration of the macula cause an increasing impairment of vision or even blindness. Macular degeneration is the number 1 cause of irreversible blindness.

In rare cases, unilateral mydriasis, heterochromia iridium, or hyphema can be observed.

leucocoria

In the differential diagnosis of leukocoria, retrolental fibrovascular membranes in the course of retinopathy of prematurity, uveitis, and toxoplasmosis must be taken into consideration

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

Retinoblastoma is diagnosed medically by examining the ocular fundus. Retinal tumor can be observed, which often contains calcium deposits and is usually the cause of retinal detachment. Also, the infiltration of the vitreous body or the anterior chamber can be visualized clearly using indirect ophthalmoscopy. Staging and planning of therapies are based on a spinal tap and a bone marrow examination. In CT scan and MRT, the intraocular expansion can be evaluated. If skeletal metastasis is suspected, scintigraphy using technetium 99m may be required.

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

Staging using the Reese-Ellsworth classification

• 

  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 the equator
• IV: Multiple tumors with a disc diameter larger than 10 mm or lesion extending anteriorly to the ora serrata
• V: Tumor involving more than half of the retina or vitreous seeding

Therapy of Retinoblastoma

Conservative treatment,i.e. bulb preservative treatment is only indicated if it is possible to obtain a certain degree of vision. These treatments include photocoagulation, cryotherapy, and external beam radiotherapy since the tumor is sensitive to radiation. Regular checkups are crucial, since osteosarcoma may form in the area where radiation was carried out, or a radiogenic cataract may develop. Better treatment measure is brachytherapy using episcleral plaque radiation. For this procedure, an applicator containing ruthenium-106 is patched onto the sclera and removed after the cumulative dose has been applied. Adjuvant chemotherapy is recommended when the tumor has metastasized.

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

Enucleation of the eye is a valid option in patients with unilateral disease. In patients with bilateral retinoblastoma, the less affected eye is saved and treated conservatively, while the other eye can be enucleated.

Special Types of Retinoblastoma

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 hereditary retinoblastoma combined with a brain tumor. However, the brain tumor is not due to metastasis, but the histological findings are similar to those of retinoblastoma. Altogether, the trilateral retinoblastoma faces a poor prognosis.

Retinoma

The retinoma, also called retinocytoma, is a benign retinal tumor, which affects about 2% of children who carry the retinoblastoma gene mutation. It is assumed that retinoma is a precursor of retinoblastoma or retinoblastoma after ‘spontaneous regression’ since their histology is quite similar.

Prognosis of Retinoblastoma

The five-year survival rate is about 97%. The prognosis is poor if the retinoblastoma is bilateral or the choroid or optic nerve is infiltrated beyond the resection border. The prognosis is clearly poorer if distant metastases are found with the sole curative approach being high-dose chemotherapy combined with a reinfusion of stem cells.

Follow-Up Treatment of Retinoblastoma

If one parent has had bilateral or multifocal retinoblastoma, the patient is generally considered a carrier of a constitutional mutation, which is inherited autosomal dominant. If the 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 2 weeks of its life. Furthermore, the frequent examination of the ocular fundus should be performed by a pediatric ophthalmologist until the age of 3.

Descendants or brothers or sisters of patients having a sporadic type of unilateral retinoblastoma do not have higher disease risks. However, unilateral retinoblastoma caused by germline mutations must be ruled out.

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