Retinoblastoma: A review on the causes, diagnosis, and current approaches of treatment

Tijesunimi Fakunle, Neha Shiju, Enegbuma Angelica Onagiekhuwemhe, Krisha Patel, Muzaina Shahid

Abstract

Retinoblastoma is the most common intraocular malignancy in children, arising from retinal cells and caused by genetic mutations and environmental factors. This review aims to provide a comprehensive overview of the causes, diagnosis, and current treatment approaches for retinoblastoma. Understanding these aspects is critical for advancing early detection and improving treatment strategies, ultimately enhancing survival rates and quality of life for affected children. The research methodology involved an extensive review of recent literature, including studies on imaging, molecular diagnostics, and emerging therapies. The findings underscore the significance of personalized treatment plans and the need for ongoing research to optimize outcomes for patients. This paper concludes by highlighting the potential for new therapeutic advancements in retinoblastoma management.

Introduction

Retinoblastoma is a significant challenge in pediatric oncology, usually affecting young children under the age of five. This aggressive intraocular malignancy arises from the developing cells of the retina. Instead of maturing, these cells grow uncontrollably, forming a tumor that can threaten both vision and life. 

Retinoblastoma occurs due to a mutation in the RB1 gene, which is located on the long arm of chromosome 13 at position 13q14. For a tumor to form, both copies of the RB1 gene must be mutated. In cases where both eyes are affected (bilateral retinoblastoma), there’s a 98% chance that the mutation is inherited. However, only about 5% of retinoblastoma cases have a family history. Most cases, around 95%, occur randomly, with 60% of these involving just one eye and no inherited gene mutation. The other cases involve inherited mutations that lead to multiple tumors (Ishaq and Patel). 

Recent studies have shown that the diagnosis of retinoblastoma mainly relies on recognizing specific clinical signs and using non-invasive imaging techniques. The most common sign is leukocoria, where a white reflection appears in the pupil due to tumor growth and calcification. This is often followed by strabismus, as the tumor affects central vision. In more advanced stages, changes in iris color, an enlarged cornea, or non-infective orbital inflammation may also be seen. Diagnosis is confirmed through indirect ophthalmoscopy,  ocular ultrasound, and MRI (Gu et al.).

Treatment of retinoblastoma has undergone significant advancements in recent years. Landmark progress in local drug delivery methods, including refined techniques for intravitreal chemotherapy injection and ophthalmic artery chemosurgery, has facilitated the preservation of the eye globe, a feat not achievable with prior systemic chemotherapy or external beam irradiation. Emerging therapeutic strategies, such as novel pharmaceuticals, oncolytic viruses, and immunotherapy, show considerable promise in treating intraocular retinoblastoma. Additionally, ongoing research into tumor dissemination patterns and local drug delivery methods may pave the way for groundbreaking treatments targeting metastatic disease (Schaiquevich et al.). 

Diagnoses and Statistics

Retinoblastoma is a rare malignant tumor that typically occurs in the retina of young children. Early diagnosis is crucial for effective treatment and to prevent loss of vision or metastasis. Diagnosis often begins with a detailed medical history and physical examination. A key diagnostic indicator is leukocoria, a white reflex in the pupil, which is often detected by parents or during pediatric check-ups. Additional clinical signs may include strabismus (misalignment of the eyes), redness, or swelling. 

Advanced diagnostic techniques are employed to confirm the presence of retinoblastoma. Ophthalmoscopy, a procedure that allows a detailed examination of the retina, is the primary diagnostic tool (“Ophthalmoscopy: Purpose, Procedure, and Risks.”). It is often performed under anesthesia in children. Ultrasound of the eye can help visualize the tumor's size and location, while Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) scans are used to assess the extent of the disease, including any potential spread to surrounding tissues or the brain (“Magnetic Resonance Imaging (MRI)”). Genetic testing is also essential, as retinoblastoma can be hereditary, with mutations in the RB1 gene being a significant marker (“Retinoblastoma - Diagnosis and Treatment”).

Statistically, retinoblastoma occurs in approximately 1 in 15.000 to 20,000 live births worldwide. Early detection and advancements in treatments have significantly improved survival rates particularly in developed countries. The overall survival rate for retinoblastoma is over 95% in high resource settings, although outcomes vary globally due to disparities in healthcare access and early detection programs. (“Key Statistics for Retinoblastoma.”)

Assessments and Measures

Following diagnoses, the severity and stage of retinoblastoma are assessed using various classification systems. The International Classification of Retinoblastoma (ICRB) is commonly used, categorizing the disease into five groups (A to E) based on the size, location, and potential for vision preservation (“Stages of Retinoblastoma (Classification)”). Group A represents the least severe cases, while Group E includes tumors with extensive damage and poor prognosis for retaining the eye. 

Treatment 

Retinoblastoma can be treated in various ways and the treatment is often successful if the cancer is detected early on. The treatment received depends on the size of the cancer, location of the cancer, the rate at which it spreads and the child’s age and health ("Treatment for retinoblastoma"). Often treatment options are not limited to one, rather a combination of treatments are chosen.

Laser treatment

Laser treatment uses a beam of light that is focused into the pupil to kill cancer cells. This treatment is however only successful for small tumors ("Treatment for retinoblastoma"). Laser therapy is further divided into two types. The first one being photocoagulation, and the second one being thermotherapy ("Treating retinoblastoma").

Photocoagulation laser therapy involves the use of light at different strengths. This also kills the blood vessels that perpetuate the cancer ("Treating retinoblastoma").

Thermotherapy is also referred to as transpupillary therapy (TTT) or heat therapy. This form of laser treatment uses infrared light which uses heat to burn the cancer cells and kill them.

Cryotherapy (freezing therapy)

Another treatment option is cryotherapy, which is also referred to as freezing therapy. Cryotherapy essentially freezes the cancer cells and kills them. It can be thought of as the opposite of thermotherapy which uses heat to kill the cancer cells. Cryotherapy is executed using a metal probe that is extremely low in temperature ("Treating retinoblastoma"). The probe freezes the cancer cells, killing them. An advantage of cryotherapy is that it is local. This means that the therapy only targets areas in which cancer is present, doing no harm to other healthy cells. However, cryotherapy is only used for small tumors and if the tumor is present on the outer edge of the retina ("Treatment for retinoblastoma").

Radiotherapy

Radiotherapy uses radiation to kill cancer cells. This treatment is only used if the tumor is small and other treatments have not been effective ("Treatment for retinoblastoma"). Radiotherapy is further divided into two types. The first one being brachytherapy, and the second one being proton beam therapy ("Treating retinoblastoma").

Brachytherapy involves the placement of a plaque (a small radioactive disc). It is stitched to the cancer and remains there for a few days. The plaque supplies a high amount of radiation to the area covered. It is also often called localized radiotherapy since it only targets the affected area ("Treating retinoblastoma").

("Treating retinoblastoma").

The second type of treatment, proton beam therapy, is a type of external radiotherapy. This is employed if the cancer has spread to the optic nerves or eye socket ("Treating retinoblastoma"). This type of therapy uses proton beams to precisely target the cancer. Due to its targeting and precise nature, it only affects the harmed area.

Chemotherapy

Another treatment option is chemotherapy. Chemotherapy essentially shrinks the tumor using drugs. This can be done in various different ways, for instance, through the bloodstream (intravenously), through a blood vessel, or an injection into the eye ("Treating retinoblastoma"). Chemotherapy is done if the cancer is large and may have a chance of spreading. 

Surgery

Surgery is usually a last resort, often done if the above treatment options have not been working or if the cancer is spreading rapidly ("Treatment for retinoblastoma"). Surgery involves the removal of the eye and it will be replaced with an artificial eye. The artificial eye will have a prosthesis to cover the implant ("Treating retinoblastoma").

("Treating retinoblastoma").

Medical Professions Required

Retinoblastoma requires a team of different medical professionals in order to effectively manage the cancer. This team consists of an ophthalmologist, pediatric oncologist, ocular pathologist, geneticist and allied health professionals (Ishaq and Patel).

An ophthalmologist deals with eye care, diagnosing and treating eye diseases. They perform surgery as well as doing research into the field of ophthalmology (Churchill and Gudgel). Becoming an ophthalmologist is different in every country, however in the U.S. you would need to complete a bachelor’s degree, 4 years of medical school, a one-year internship and finally a 36-month residency (Indeed Editorial Team). After successfully completing this, it is possible to practice. An ophthalmologist earns a salary between $277,000 and $377,078 in the U.S. ("Physician - Ophthalmology").

A pediatric oncologist diagnoses and treats children and teenagers who face cancer, blood cell diseases and bleeding and clotting disorders (Savelli and Stoffman). In order to become a pediatric oncologist, one has to complete medical school, three years of residency in pediatrics and three years of fellowship training in pediatric hematology/oncology (Savelli and Stoffman). Finally, to practice, it is essential to be certified by the American board of pediatrics or an international board. A pediatric oncologist earns a salary of $170,000 on average (Z).

An ocular pathologist examines and diagnoses eye tissue diseases. They look at both surgical (biopsy) and non-surgical (removed eye specimens)  ("Ophthalmic Pathology"). Becoming an ocular pathologist requires completion of the 4-year medical school, one year internship, three years of residency and finally one or two years of subspecialty training ("Training and Certification"). An ocular pathologist generally earns an average of $157,115 ("Ophthalmic Pathologist").

Opthomologists, pediatric oncologists and ocular pathologists are the main medical professions required for retinoblastoma. The other two, a geneticist and allied health professionals can provide aid and some insight. A geneticist studies genes and hereditary conditions (Rowland). In terms of retinoblastoma, they could look into the child’s family and the conditions they had. Allied health professionals help with the identification and assessment of diseases, serving as a support system for the other professionals ("Allied health").

Physical impacts and Long-Term Considerations

The major physical consequence of retinoblastoma is vision loss, which can range from partial to total loss of sight in the afflicted eye(s). Enucleation, or surgical removal of the eye, may be used in extreme circumstances to prevent cancer from spreading. Some children with retinoblastoma may lose sight in one or both eyes, while others may experience mild visual alterations. Losing part or all of a child's vision can be stressful and significantly influence their lives. It takes time to adapt to eyesight changes. Children with peripheral vision issues may need to rotate their heads to look on the side affected by retinoblastoma. Children who couldn't see out of one eye due to cancer before it was removed frequently adjust more quickly because there is no sudden change to their vision (Canadian Cancer Society / Société Canadienne, n.d.).

Moreover with significant breakthroughs in treatment over the past decades, most children treated for retinoblastoma can now expect to live normal lives. However, some cancer therapies can have an impact on a child's health later in life, thus monitoring for health impacts as they age has been increasingly important in recent years. Young people who have been treated for retinoblastoma are at risk for several potential long-term complications of their cancer therapy. The probability of late effects is determined by several factors, including the specific therapies employed, treatment dosages, the kind of retinoblastoma (heritable or non-heritable), and the child's age at the time of treatment. These late impacts may include reduced or loss of vision in the damaged eye(s), bone deformities surrounding the eye, decreased renal function, slowed or delayed growth and development, and so on. (Living as a Retinoblastoma Survivor, n.d.).  For example, children who have had brain radiation therapy are at risk of developing growth hormone (GH) deficit, which can also impact reproductive hormone levels. Chemotherapy may induce heart and renal issues. Radiation treatment and chemotherapy may raise a child's chance of having a second cancer later in life (Canadian Cancer Society / Société Canadienne, n.d.).

Emotional impact and social challenges

Retinoblastoma has a profound emotional and psychological impact on  children and their family. Financial hardship, commuting to and living near the cancer center, and the necessity for family members to take time off work are all frequent family issues. The stress of a cancer diagnosis, along with the need of extensive therapy, can also cause significant anxiety and emotional strain. Some children may have emotional or psychological concerns that should be addressed during and after treatment (Living as a Retinoblastoma Survivor, n.d.). 

Also, depending on their age, young people may also experience difficulties with regular functioning and schoolwork as a result of visual changes that influence reading, writing, capacity to complete schoolwork, and mobility. Children may have low self-esteem as a result of obvious changes such as losing an eye or having scars. Psychological assistance is critical in helping children and their families negotiate these issues and preserve mental health during the treatment process (Canadian Cancer Society / Société Canadienne, n.d.). These sorts of problems may frequently be resolved with assistance and encouragement. Doctors and other members of the health-care team might propose specialized programs and services to assist children during and after treatment. Social workers and other specialists at treatment facilities can also assist families in sorting through these challenges (Living as a Retinoblastoma Survivor, n.d.).

Discussion

Retinoblastoma is a serious condition and demands a comprehensive review and strategy to manage the physical, emotional, and social ramifications associated with this condition. Current therapies such as laser therapy, cryotherapy, radiotherapy, and chemotherapy have made large strides in terms of efficient intervention but challenges persist. The foremost physical concern though will always be safeguarding the vision and preservation of the child's life. 

In terms of diagnosis, early detection techniques like ophthalmoscopy, ultrasound, and genetic testing shows the importance of early intervention in enhancing patient outcomes. The use of imaging technologies has also provided accurate information in terms of determining the extent of the disease, which is essential for developing unique  treatment strategies. Moreover, genetic testing is vital for recognizing hereditary forms of the disease, which is important for family planning and facilitating early intervention in children.

In addition to the physical concerns, the psychological and social aspects of retinoblastoma hold importance. The diagnosis of a serious illness in a young child like this can be profoundly distressing for families, leading to emotional and financial strain making psychological support essential. Emotional assistance is particularly crucial in instances where the child undergoes physical changes, such as the loss of an eye, impacting self-esteem. Highlighting the need for allied health professionals, including social workers and psychologists,to  address these social implications.

Overall, the management of retinoblastoma requires a multifaceted  strategy that not only prioritizes medical interventions but also considers the long-term physical, emotional, and social impacts on a child. This highlights the main reason why we choose to explore retinoblastoma, its rare unique intersections with genetics, oncology, and ophthalmology, offer a rich outlook into both early detection and innovative treatment strategies. Its further impact on young children is also huge and the advancements in preserving vision and life make it a compelling subject for research.

Conclusion 

In order to properly manage the complications of retinoblastoma, a thorough and multidisciplinary approach is required. This review highlights the knowledge and management of retinoblastoma by offering a thorough overview of the diagnostic developments, the condition's impact, and current therapeutic approaches. The majority of instances of retinoblastoma are caused by genetic abnormalities, specifically inherited mutations in the RB1 gene. In making an initial diagnosis, a comprehensive medical history, physical examination, and identification of critical indicators are usually necessary. And to assess its severity, advanced diagnostic methods such as ophthalmoscopy, ultrasonography, MRI, and genetic testing are essential. According to the International Classification of Retinoblastoma (ICRB), the course of treatment for a tumor can vary depending on its size, location, and the general health of the kid. It might involve radiation, chemotherapy, cryotherapy, laser treatment, or even surgery in certain situations. 

Based on the particulars of each case, these therapies are chosen and frequently combined to get the greatest results. Also, a multidisciplinary team consisting of ophthalmologists, pediatric oncologists, ocular pathologists, geneticists, and allied health workers manages retinoblastoma. Every expert makes a distinct contribution to the patient's diagnosis, course of therapy, and aftercare. Physical effects of retinoblastoma include partial or complete loss of vision, requiring adjustments and, in extreme situations, enucleation of the afflicted eye. Long-term problems emphasize the need for ongoing monitoring and treatment, since they may include vision impairment, growth challenges, and an increased risk of subsequent malignancies. Children and their families deal with a lot of emotional and social difficulties, such as financial hardship, psychological discomfort, and even interruptions to everyday life and education.

In summary, retinoblastoma presents both substantial obstacles and chances for important assistance and action. While many children's quality of life and survival rates have increased due to advancements in diagnosis and treatment techniques, continued focus on the social, emotional, and physical aspects is still vital. The combined efforts of a diversified medical team and support systems are critical in negotiating the intricacies of retinoblastoma and providing the best possible results for afflicted youths.

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