Retinoblastoma | |
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A pathology specimen of a retinoblastoma tumor from an enucleated eye of a 3-year-old female | |
Specialty | Neuro-oncology |
Symptoms | Leukocoria seen in patient's pupil in photos Poor vision One or both eyes turning inward or outward Eye pain [1] |
Usual onset | Under 3 years old [1] |
Treatment | Surgery (including eye removal in advanced cases) Chemotherapy (after surgery in cases of metastasis) Focal therapy [1] |
Frequency | ~250–300 children diagnosed annually (United States) [1] |
Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, [2] the light-detecting tissue of the eye. [3] 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. [4] [5]
Though most children in high income countries survive this cancer, [2] they may lose their vision in the affected eye(s) [6] or need to have the eye removed. [2]
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 (retinoblastoma protein). [7]
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. [3]
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 (when light is reflected by the tumor, the regular view of the red retina is blocked). The retinoblastoma may be visible as a whitish, translucent mass. [8] 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. [9]
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. [5] 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, [10] commonly referred to as "cross-eyed" or "wall-eyed" (strabismus). Retinoblastoma presents with advanced disease in developing countries and eye enlargement is a common finding. [11]
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 (EUA). A white eye reflection is not always a positive indication of retinoblastoma and can be caused by light being reflected badly [12] or by other conditions such as Coats' disease. [13]
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" (leukocoria). [14]
Mutation of genes, found in chromosomes, can affect the way in which cells grow and develop within the body. [15] Alterations in RB1 or MYCN can give rise to retinoblastoma.
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. [15] Although RB1 interacts with over 100 cell proteins, [15] 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. [15]
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. [16]
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 (PNETs) with a dismal outcome; retinoblastoma concurrent with a PNET is known as trilateral retinoblastoma. [17] 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. [18]
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 (germline or constitutional), which will then be present in all cells in the body. The second “hit” results in the loss of the remaining normal allele (gene) and occurs within a particular retinal cell. [19] In the sporadic, nonheritable form of retinoblastoma, both mutational events occur within a single retinal cell after fertilization (somatic events); sporadic retinoblastoma tends to be unilateral.
Several methods have been developed to detect the RB1 gene mutations. [20] [21] Attempts to correlate gene mutations to the stage at presentation have not shown convincing evidence of a correlation. [22]
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. [23] 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. [24] [25] 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. [26]
Screening for retinoblastoma should be part of a "well baby" screening for newborns during the first 3 months of life, to include: [27]
The two forms of the disease are a heritable form and nonheritable form (all cancers are considered genetic in that mutations of the genome are required for their development, but this does not imply that they are heritable, or transmitted to offspring). Approximately 40% of patients have a heritable form of retinoblastoma, carrying a mutation in the RB1 gene. [28] 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.[ citation needed ]
In about two-thirds of cases, [29] only one eye is affected (unilateral retinoblastoma); in the other third, tumors develop in both eyes (bilateral retinoblastoma). The number and size of tumors on each eye may vary. In certain cases, the pineal gland or the suprasellar or parasellar region (or in very rare cases other midline intracranial locations) is also affected (trilateral retinoblastoma). The position, size, and quantity of tumors are considered when choosing the type of treatment for the disease.[ citation needed ]
If the eye examination is abnormal, further testing may include imaging studies, such as computerized tomography (CT), magnetic resonance imaging (MRI), and ultrasound. [30] 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.[ citation needed ]
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, [31] and fleurettes from photoreceptor differentiation. [32]
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 (future) siblings and offspring. It may run in the family.
Traditional ultrasound B scan can detect calcifications in the tumour while high-frequency ultrasound B scan is able to provide higher resolution than the traditional ultrasound and determine the proximity of the tumour with front portion of the eye. MRI scan can detect high-risk features such as optic nerve invasion; choroidal invasion, scleral invasion, and intracranial invasion. CT scan is generally avoided because radiation can stimulate the formation of more eye tumours in those with RB1 genetic mutation. [37]
In order to properly diagnose retinoblastoma, there must be guidelines to follow to properly classify the risk of the tumor. The Reese Ellsworth Classification System, by Dr. Algernon Reese and Dr. Robert Ellsworth, is universally used to determine the size, location, and multi-focality of the tumor. [38] The system was originally used to decide the best treatment result by using external beam radiotherapy, as well as, the likeliness of salvaging the globe of the eye. Due to chemotherapy not being part of the Reese Ellsworth Classification System, there needed to be an updated classification system to foresee the treatment outcomes of chemotherapy. The International Classification for Intraocular Retinoblastoma is now the current system being used, and it was created by Murphree and associates. [38] According to Reese and Ellsworth, there were different groups that had various features in order to classify the globe salvage as very favorable to the category of very unfavorable. In order to salvage the affected eye, the disc diameter had to be around 4DD and behind the equator to have higher favorability. If the tumor was around ten in disc diameter and involved roughly 50% of the retina, it was considered unfavorable to salvage the globe which could result in enucleation. According to Murphree, the different groups were classified from very low risk to very high risk which was determined by features of the given tumor. Very low risk means that the tumor has to be less than 3mm and there must be no seeding of the vitreous or sub-retinal area. When a patient is very high risk, the tumor presents itself with multiple features and is going to have to be treated with conservative treatment modalities or enucleation. [39]
Group | Clinical Features |
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A Very low risk | All tumors are 3mm or smaller, confined to the retina, and located at least 3mm from the foveola and 1.5mm from the optic nerve. No vitreous or subretinal seeding |
B Low risk | Retinal tumors may be any size or location not in Group A, No vitreous or subretinal seeding allowed. A small cuff of subretinal fluid extending no more than 5mm from the base of the tumor is allowed |
C Moderate risk | Eyes with only focal vitreous or subretinal seeding and discrete retinal tumors of any size and location. Vitreous or subretinal seeding may extend no more than 3mm from the tumor. Up to one quadrant of subretinal fluid may be present |
D High risk | Eyes with diffuse vitreous or subretinal seeding and/or massive, nondiscrete endophytic or exophytic disease. More than one quadrant of retinal detachment |
E Very high risk eyes | Eyes with one or more of the following: Irreversible neovascular glaucoma Massive intraocular hemorrhage Aseptic orbital cellulitis Phthisis or pre-phthisis Tumor anterior to anterior vitreous face Tumor touching the lens Diffuse infiltrating retinoblastoma |
International Classification for Intraocular Retinoblastoma [38] [39]
The priority of retinoblastoma treatment is to preserve the life of the child, then to preserve vision, and then to minimize complications or side effects of treatment. The exact course of treatment depends on the individual case and is decided by the ophthalmologist in discussion with the paediatric oncologist. [40] Correct treatment also depends on the mutation type, whether it is a germline RB1 mutation, a sporadic RB1 mutation or MYCN amplification with functional RB1. [41] Children with involvement of both eyes at diagnosis usually require multimodality therapy (chemotherapy, local therapies).
The various treatment modalities for retinoblastoma includes: [40] [42] [43]
In the developed world, retinoblastoma has one of the best cure rates of all childhood cancers (95-98%), with more than 90% of sufferers surviving into adulthood. In the UK, around 40 to 50 new cases are diagnosed each year. [50] Good prognosis depends upon early presentation of the child in health facility. [51] Late presentation is associated with a poor prognosis. [52] Survivors of hereditary retinoblastoma have a higher risk of developing other cancers later in life. About 5% of cases require enucleation.
Retinoblastoma presents with cumulative lifetime incidence rate of one case of retinoblastoma per 18000 to 30000 live births worldwide. [53] 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. [54]
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. [55] In the UK, bilateral cases usually present within 14 to 16 months, while diagnosis of unilateral cases peaks between 24 and 30 months.
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.
Von Hippel–Lindau disease (VHL), also known as VonHippel–Lindau syndrome, is a rare genetic disorder with multisystem involvement. It is characterized by visceral cysts and benign tumors with potential for subsequent malignant transformation. It is a type of phakomatosis that results from a mutation in the Von Hippel–Lindau tumor suppressor gene on chromosome 3p25.3.
Retinitis pigmentosa (RP) is a member of a group of genetic disorders called inherited retinal dystrophy (IRD) that cause loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision. As peripheral vision worsens, people may experience "tunnel vision". Complete blindness is uncommon. Onset of symptoms is generally gradual and often begins in childhood.
Norrie disease is a rare X-linked recessive genetic disorder that primarily affects the eyes and almost always leads to blindness. It is caused by mutations in the Norrin cystine knot growth factor gene, also referred to as Norrie Disease Pseudoglioma (NDP) gene. Norrie disease manifests with vision impairment either at birth, or within a few weeks of life, following an ocular event like retinal detachment and is progressive through childhood and adolescence. It generally begins with retinal degeneration, which occurs before birth and results in blindness at birth (congenital) or early infancy, usually by 3 months of age.
The two-hit hypothesis, also known as the Knudson hypothesis, is the hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change. It was first formulated by Alfred G. Knudson in 1971 and led indirectly to the identification of tumor suppressor genes. Knudson won the 1998 Albert Lasker Clinical Medical Research Award for this work.
A blastoma is a type of cancer, more common in children, that is caused by malignancies in precursor cells, often called blasts. Examples are nephroblastoma, medulloblastoma, and retinoblastoma. The suffix -blastoma is used to imply a tumor of primitive, incompletely differentiated cells, e.g., chondroblastoma is composed of cells resembling the precursor of chondrocytes.
Uveal melanoma is a type of eye cancer in the uvea of the eye. It is traditionally classed as originating in the iris, choroid, and ciliary body, but can also be divided into class I and class II. Symptoms include blurred vision, loss of vision, and photopsia, but there may be no symptoms.
Stargardt disease is the most common inherited single-gene retinal disease. In terms of the first description of the disease, it follows an autosomal recessive inheritance pattern, which has been later linked to bi-allelic ABCA4 gene variants (STGD1). However, there are Stargardt-like diseases with mimicking phenotypes that are referred to as STGD3 and STGD4, and have a autosomal dominant inheritance due to defects with ELOVL4 or PROM1 genes, respectively. It is characterized by macular degeneration that begins in childhood, adolescence or adulthood, resulting in progressive loss of vision.
An eye neoplasm is a tumor of the eye. A rare type of tumor, eye neoplasms can affect all parts of the eye, and can either be benign or malignant (cancerous), in which case it is known as eye cancer. Eye cancers can be primary or metastatic cancer. The two most common cancers that spread to the eye from another organ are breast cancer and lung cancer. Other less common sites of origin include the prostate, kidney, thyroid, skin, colon and blood or bone marrow.
Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain.
Intraocular lymphoma is a rare malignant form of eye cancer. Intraocular lymphoma may affect the eye secondarily from a metastasis from a non-ocular tumor or may arise within the eye primarily. PIOL is a subset of primary central nervous system lymphoma (PCNSL). PCNSL are most commonly a diffuse large B-cell immunohistologic subtype of non-Hodgkin's lymphoma according to the World Health Organization (WHO) classification of lymphomas. The most common symptoms of PIOL include blurred or decreased vision due to tumor cells in the vitreous. Most cases of PIOL eventuate to central nervous system involvement (PCNSL) while only 20% of PCNSL lead to intraocular (PIOL) involvement. PIOL and PCNSL remain enigmas because both structures are immunologically privileged sites and so do not normally have immune cells trafficking through these structures. What is more, while the vast majority of PCNSL in patients with acquired immune deficiency syndrome (AIDS) is related to the Epstein-Barr virus (EBV), the development of PCNSL and PIOL in immunocompetent patients is unknown and shows no general relation to infectious DNAs.
Thaddeus P. Dryja is an American ophthalmologist and geneticist known for his role in the 1986 discovery of the retinoblastoma (Rb) tumor suppressor gene. and the 1990 discovery of mutations in the rhodopsin gene as the cause of autosomal dominant retinitis pigmentosa . He was the David G. Cogan Professor of Ophthalmology at Harvard University and was the Global Head of Ophthalmology Research at Novartis. He was elected a member of the National Academy of Sciences in 1996.
Pineoblastoma is a malignant tumor of the pineal gland. A pineoblastoma is a supratentorial midline primitive neuroectodermal tumor. Pineoblastoma can present at any age, but is most common in young children. They account for 0.001% of all primary CNS neoplasms.
Persistent fetal vasculature(PFV), also known as persistent fetal vasculature syndrome (PFVS), and until 1997 known primarily as persistent hyperplastic primary vitreous (PHPV), is a rare congenital anomaly which occurs when blood vessels within the developing eye, known as the embryonic hyaloid vasculature network, fail to regress as they normally would in-utero after the eye is fully developed. Defects which arise from this lack of vascular regression are diverse; as a result, the presentation, symptoms, and prognosis of affected patients vary widely, ranging from clinical insignificance to irreversible blindness. The underlying structural causes of PFV are considered to be relatively common, and the vast majority of cases do not warrant additional intervention. When symptoms do manifest, however, they are often significant, causing detrimental and irreversible visual impairment. Persistent fetal vasculature heightens the lifelong risk of glaucoma, cataracts, intraocular hemorrhages, and Retinal detachments, accounting for the visual loss of nearly 5% of the blind community in the developed world. In diagnosed cases of PFV, approximately 90% of patients with a unilateral disease have associated poor vision in the affected eye.
Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.
Targeted molecular therapy for neuroblastoma involves treatment aimed at molecular targets that have a unique expression in this form of cancer. Neuroblastoma, the second most common pediatric malignant tumor, often involves treatment through intensive chemotherapy. A number of molecular targets have been identified for the treatment of high-risk forms of this disease. Aiming treatment in this way provides a more selective way to treat the disease, decreasing the risk for toxicities that are associated with the typical treatment regimen. Treatment using these targets can supplement or replace some of the intensive chemotherapy that is used for neuroblastoma. These molecular targets of this disease include GD2, ALK, and CD133. GD2 is a target of immunotherapy, and is the most fully developed of these treatment methods, but is also associated with toxicities. ALK has more recently been discovered, and drugs in development for this target are proving to be successful in neuroblastoma treatment. The role of CD133 in neuroblastoma has also been more recently discovered and is an effective target for treatment of this disease.
Autoimmune retinopathy (AIR) is a rare immunological disease in which the patient's immune system attacks proteins in the retina, leading to loss of vision. Researchers do not yet fully understand the disease, but it may be the result of cancer or cancer chemotherapy. Autoimmune retinopathy is an autoimmune condition characterized by vision loss, blind spots, and visual field abnormalities. Autoimmune retinopathy can be divided into paraneoplastic (PAIR) or non-paraneoplastic (nPAIR). The nPAIR division can be further divided into cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR). The condition is associated with retinal degeneration, when autoimmune antibodies recognize retinal proteins as antigens and target them, leading to retinal degeneration.
J. William Harbour is an American ophthalmologist, ocular oncologist and cancer researcher. He is Chair of the Department of Ophthalmology at the University of Texas Southwestern Medical Center in Dallas. He previously served as the vice chair and director of ocular oncology at the Bascom Palmer Eye Institute and associate director for basic science at the Sylvester Comprehensive Cancer Center of the University of Miami's Miller School of Medicine.
Congenital blindness refers to blindness present at birth. Congenital blindness is sometimes used interchangeably with "Childhood Blindness." However, current literature has various definitions of both terms. Childhood blindness encompasses multiple diseases and conditions present in ages up to 16 years old, which can result in permanent blindness or severe visual impairment over time. Congenital blindness is a hereditary disease and can be treated by gene therapy. Visual loss in children or infants can occur either at the prenatal stage or postnatal stage. There are multiple possible causes of congenital blindness. In general, 60% of congenital blindness cases are contributed from prenatal stage and 40% are contributed from inherited disease. However, most of the congenital blindness cases show that it can be avoidable or preventable with early treatment.
Cancer Associated Retinopathy (CAR) also known as Carcinoma Associated Retinopathy is an immune-mediated disease affecting the retina of the eye. It is a paraneoplastic type autoimmune retinopathy associated with cancer that can cause blindness. It can be seen in association with various types of cancers. It can be treated with a combination of chemotherapy and immunosuppression.