Retinoblastoma


Retinoblastoma is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cases are first detected in those under 3 years old.
Though most children in high income countries survive this cancer, they may lose their vision in the affected eye or need to have the eye removed.
Almost half of children with retinoblastoma have a hereditary genetic defect associated with it. In other cases, retinoblastoma is caused by a congenital mutation in the chromosome 13 gene 13q14.

Epidemiology

Retinoblastoma is the most common primary intraocular malignancy of childhood. It presents with cumulative lifetime incidence rate of one case of retinoblastoma per 18000 to 30000 live births worldwide. A higher incidence is noted in developing countries, which has been attributed to lower socioeconomic status and the presence of human papilloma virus sequences in the retinoblastoma tissue.
Global incidence and prevalence of retinoblastoma increased between 1990 and 2021, with incident cases rising from 4,674 to 6,275 and the age-standardized incidence rate increasing from 0.076 to 0.094 per 100,000 population. Over the same period, global mortality and disability-adjusted life years declined, indicating improved survival, while substantial regional disparities persisted, with the highest burden in Eastern Sub-Saharan Africa and the lowest in Australasia.
Almost 80% of children with retinoblastoma are diagnosed before three years of age and diagnosis in children above six years of age is extremely rare. In the UK, bilateral cases usually present within 14 to 16 months, while diagnosis of unilateral cases peaks between 24 and 30 months.

Signs and symptoms

Retinoblastoma is the most intrusive intraocular cancer among children. The chance of survival and preservation of the eye depends fully on the severity. Retinoblastoma is extremely rare as there are only about 200 to 300 cases every year in the United States. Globally, only 1 in about 15,000 children have this malignancy, though rates continue to increase.
Intraocular malignancies are relatively more frequently treated than extraocular malignancies, likely due to a relatively earlier detection and subsequent treatment. Pediatricians may screen infants with annual vision tests, in which anomalies can be detected. During a red reflex test, light from an ophthalmoscope goes through transparent parts of the eye and reflects off the ocular fundus. If retinoblastoma is present, it may partially or fully impede light transversing this path. This may result in an abnormal red reflex or leucocoria, which can be a common indicator of retinoblastoma. The retinoblastoma may be visible as a whitish, translucent mass. If the tumor has not spread and is contained within the eye, chances of successful treatment are favorable. If initial signs are ignored or diagnosis is significantly delayed, outcomes and prognosis worsen. The effects of retinoblastoma may spread outside the eye, sometimes resulting in proptosis. Retinoblastoma that has spread may be significantly more difficult to treat.
The most common and obvious sign of retinoblastoma is an abnormal appearance of the retina as viewed through the pupil, the medical term for which is leukocoria, also known as amaurotic cat's eye reflex. Other signs and symptoms include deterioration of vision, a red and irritated eye with glaucoma, and faltering growth or delayed development. Some children with retinoblastoma can develop a squint, commonly referred to as "cross-eyed" or "wall-eyed". Retinoblastoma presents with advanced disease in developing countries and eye enlargement is a common finding.
Depending on the position of the tumors, they may be visible during a simple eye examination using an ophthalmoscope to look through the pupil. A positive diagnosis is usually made only with an examination under anesthetic. A white eye reflection is not always a positive indication of retinoblastoma and can be caused by light being reflected badly or by other conditions such as Coats' disease.
The presence of the photographic fault red eye in only one eye and not in the other may be a sign of retinoblastoma. A clearer sign is "white eye" or "cat's eye".

Cause

Mutation of genes, found in chromosomes, can affect the way in which cells grow and develop within the body. Alterations in RB1 or MYCN can give rise to retinoblastoma.

RB1

In children with the heritable genetic form of retinoblastoma, a mutation occurs in the RB1 gene on chromosome 13. RB1 was the first tumor suppressor gene cloned. Although RB1 interacts with over 100 cell proteins, its negative regulator effect on the cell cycle principally arises from binding and inactivation of the transcription factor E2F, thus repressing the transcription of genes which are required for the S phase.
The defective RB1 gene can be inherited from either parent; in some children, however, the mutation occurs in the early stages of fetal development. The expression of the RB1 allele is autosomal dominant with 90% penetrance.
Inherited forms of retinoblastomas are more likely to be bilateral. In addition, inherited uni- or bilateral retinoblastomas may be associated with pineoblastoma and other malignant midline supratentorial primitive neuroectodermal tumors with a dismal outcome; retinoblastoma concurrent with a PNET is known as trilateral retinoblastoma. A 2014 meta-analysis showed that 5-year survival of trilateral retinoblastoma increased from 6% before 1995 to 57% by 2014, attributed to early detection and improved chemotherapy.
The development of retinoblastoma can be explained by the two-hit model. According to the two-hit model, both alleles need to be affected, so two events are necessary for the retinal cell or cells to develop into tumors. The first mutational event can be inherited, which will then be present in all cells in the body. The second "hit" results in the loss of the remaining normal allele and occurs within a particular retinal cell. In the sporadic, nonheritable form of retinoblastoma, both mutational events occur within a single retinal cell after fertilization ; sporadic retinoblastoma tends to be unilateral.
Several methods have been developed to detect the RB1 gene mutations. Attempts to correlate gene mutations to the stage at presentation have not shown convincing evidence of a correlation.

MYCN

Not all retinoblastoma cases are with RB1 inactivation. There are cases reported with only one RB1 mutation or even two functional RB1 alleles, which indicates other oncogenic lesions of retinoblastoma. Somatic amplification of the MYCN oncogene is responsible for some cases of nonhereditary, early-onset, aggressive, unilateral retinoblastoma. MYCN can act as a transcription factor and promotes proliferation by regulating the expression of cell cycle genes. Although MYCN amplification accounted for only 1.4% of retinoblastoma cases, researchers identified it in 18% of infants diagnosed at less than 6 months of age. Median age at diagnosis for MYCN retinoblastoma was 4.5 months, compared with 24 months for those who had nonfamilial unilateral disease with two RB1 gene mutations.

Diagnosis

Screening for retinoblastoma should be part of a "well baby" screening for newborns during the first 3 months of life, to include:
  • The red reflex: checking for a normal reddish-orange reflection from the eye's retina with an ophthalmoscope or retinoscope from about 30 cm or 1 foot, usually done in a dimly lit or dark room
  • The corneal light reflex or Hirschberg test: checking for symmetrical reflection of beam of light in the same spot on each eye when a light is shined into each cornea, to help determine whether the eyes are crossed
  • Eye examination: checking for any structural abnormalities

    Classification

The two forms of the disease are a heritable form and nonheritable form. Approximately 40% of patients have a heritable form of retinoblastoma, carrying a mutation in the RB1 gene. If no history of the disease exists within the family, the disease is labeled "sporadic", but this does not necessarily indicate that it is the nonheritable form. Bilateral retinoblastomas are commonly heritable, while unilateral retinoblastomas are commonly nonheritable.
In about two-thirds of cases, only one eye is affected ; in the other third, tumors develop in both eyes. The number and size of tumors on each eye may vary. In certain cases, the pineal gland or the suprasellar or parasellar region is also affected. The position, size, and quantity of tumors are considered when choosing the type of treatment for the disease.

Differential diagnosis

If the eye examination is abnormal, further testing may include imaging studies, such as computerized tomography, magnetic resonance imaging, and ultrasound. CT and MRI can help define the structure abnormalities and reveal any calcium depositions. Ultrasound can help define the height and thickness of the tumor. Bone marrow examination or lumbar puncture may also be done to determine any metastases to bones or the brain.

Morphology

Gross and microscopic appearances of retinoblastoma are identical in both hereditary and sporadic types. Macroscopically, viable tumor cells are found near blood vessels, while zones of necrosis are found in relatively avascular areas. Microscopically, both undifferentiated and differentiated elements may be present. Undifferentiated elements appear as collections of small, round cells with hyperchromatic nuclei; differentiated elements include Flexner-Wintersteiner rosettes, Homer Wright rosettes, and fleurettes from photoreceptor differentiation.

Genetic testing

Identifying the RB1 gene mutation that led to a child's retinoblastoma can be important in the clinical care of the affected individual and in the care of siblings and offspring. It may run in the family.
  1. Bilaterally affected individuals and 13–15% of unilaterally affected individuals, are expected to show an RB1 mutation in blood. By identifying the RB1 mutation in the affected individual, siblings, children, and other relatives can be tested for the mutation; if they do not carry the mutation, child relatives are not at risk of retinoblastoma, so need not undergo the trauma and expense of examinations under anaesthetic. For the 85% of unilaterally affected patients found not to carry either of their eye tumor RB1 mutations in blood, neither molecular testing nor clinical surveillance of siblings is required.
  2. If the RB1 mutation of an affected individual is identified, amniotic cells in an at-risk pregnancy can be tested for the family mutation; any fetus that carries the mutation can be delivered early, allowing early treatment of any eye tumors, leading to better visual outcomes.
  3. For cases of unilateral retinoblastoma where no eye tumor is available for testing, if no RB1 mutation is detected in blood after high-sensitivity molecular testing, the risk of a germline RB1 mutation is reduced to less than 1%, a level at which only clinic examination is recommended for the affected individual and their future offspring.