Retinoblastoma

Overview

The retina is a layer of nerve tissue that borders the interior of the rear wall of the eye. It receives light and turns it into messages that pass to the brain via the optic nerve. The impulses are decoded by the brain so that you can view the image.

Retinoblastoma is an uncommon kind of cancer that arises rapidly from immature retinal cells, the light-detecting tissue of the eye. It is the most prevalent kind of primary malignant intraocular cancer in children, and it virtually always affects young children.

Retinoblastoma definition

Retinoblastoma is a rare kind of cancer that occurs in one out of every 18000 childbirths, but it is the most prevalent primary intraocular malignancy of kids, accounting for 3% of all childhood malignancies. It is also the second most common intraocular malignant tumor, behind uveal melanoma. Survival rates in specialist treatment facilities can reach up to 95 percent, with most patients retaining their eyesight, although this figure is lower in impoverished nations.

Retinoblastoma is made up of retinoblasts (basophilic cells with hyperchromatic nuclei and scanty cytoplasm). The majority of retinoblastomas are undifferentiated, however variable degrees of differentiation are evident due to the creation of structures called rosettes. The tumor might be endophytic (in the vitreous) and seed tumor cells throughout the eye, exophytic (in the subretinal region), or have a mixed appearance.

Optic nerve invasion can develop as a result of tumor spread in the subarachnoid space and into the brain. Regional lymph nodes, the liver, the lungs, the bones, and the brain are all affected by metastatic spread.

Epidemiology

Retinoblastoma is the most prevalent primary intraocular tumor of infancy, accounting for 3% of all childhood cancers. In addition, it is the second most frequent intraocular malignant tumor. The incidence of retinoblastoma ranges from one in 14000 to one in 20000 live births.

Every year, 300 new cases are reported in the United States. Retinoblastoma affects both sexes equally and has no sexual preference. Ninety percent of cases appear before the age of three. The prevalence of the condition varies by geographical area. According to research, there are six instances per million in Mexico and four cases per million in the United States. The incidence is higher in India and Africa.

Patients with retinoblastoma have a reported survival rate of 86-92 percent. These results, however, must be seen in the context of retinoblastoma tumors. In reality, the survival rate for people with genetic mutation decreases with each decade of life.

A genomic mutation is a gene mutation that occurs in every cell of a person's body. These individuals often have bilateral disease or unilateral-multifocal disease (one eye with numerous distinctly different tumor foci). These people are predisposed to having secondary malignancies later in life.

As a result, mortality rates in these individuals are substantially greater than those in those with somatic mutations (ie, affecting one retinal cell only and unilateral-unifocal disease). Extraocular extension, either directly through the sclera or by extension along the optic nerve, is the best predictor of mortality.

Etiology 

 Retinoblastoma is caused by a mutation in the RB1 tumor suppressor gene, which is situated on the long arm of chromosome 13 at locus 14. (13q14). When both copies of the RB1 gene are mutated, a tumor develops. There is a 98 percent likelihood that the mutation in bilateral retinoblastoma is germline. Only 5% of retinoblastoma patients have a familial history.

95 percent of occurrences of retinoblastoma are spontaneous, with 60 percent of individuals having unilateral disease with no accompanying genetic mutation. The remaining individuals have germline alterations as well as the development of numerous malignancies.

• Heritable

There is a mutation in one of the alleles of the RB1 gene in all body cells in this kind of retinoblastoma. When the second allele undergoes a mutation as a result of a mutagenic event, it results in cell malignancy. Because the mutation is present in all cells, a high majority of these youngsters develop bilateral and multifocal retinoblastoma.

Patients with heritable diseases are at high risk of nonocular cancers such as pineoblastoma, osteosarcoma, soft tissue sarcomas, and melanomas, which often arise in a certain age group. The risk of second malignancy is 6%, but it increases fivefold when external beam radiation is used to treat the original tumor.

• Non-heritable

Non-heritable retinoblastomas are unilateral and not passed down via families. These patients are not at risk of developing non-ocular malignancies. It is non-heritable retinoblastoma in the event of unilateral retinoblastoma with no positive family history, and the equivalent risk in each sibling and patient's offspring is 1%. Nonhereditary unilateral retinoblastomas account for over 90% of cases.

Clinical Presentation

Patients with retinoblastoma often appear within the first year of life in the case of bilateral illness and within the first three years of life in the case of unilateral disease. It is critical to inquire about any family history of ocular cancers. The following are the most typical presenting characteristics:

• Leucocoria: (white pupillary reflex): This is the most prevalent presenting characteristic, accounting for 60% of patients.
• Strabismus: It is the second most prevalent presenting characteristic, hence all patients with childhood squint should have a fundus examination.
• Painful red eye: There may be painful redness, subsequent glaucoma, and concomitant buphthalmos.
• Inflammation: Pre-septal or orbital cellulitis-like inflammation of the orbit can also be a presenting characteristic.
• Visible extraocular growth
• Decreased vision
• Restriction of extraocular movements
• Metastatic disease: Prior to ocular involvement, metastatic illness affecting lymph nodes, liver, lungs, brain, and bones is uncommon.

Signs

• Intraretinal tumor: Intraretinal retinoblastoma is a pale, dome-shaped tumor with calcification.
• Endophytic tumor: The endophytic tumor is present in vitreous as whitish lesion and seeds in the gel.
• Exophytic tumor: Presents as whitish subretinal mass, and it causes retinal detachment.
• Hypopyon
• Strabismus

The second most prevalent style of presentation is strabismus, which arises as a result of vision loss. In all cases of infantile strabismus, a funduscopic examination via a well-dilated pupil is required.

• Hyphema
• Ocular inflammation
• Iris heterochromia
• Globe perforation
• Proptosis
• Cataract
• Glaucoma
• Anisocoria

Diagnosis

• Direct Ophthalmoscopy

The easiest test is red reflex testing with a direct ophthalmoscope, and leukocoria is plainly visible. This approach is intended to be used as a simple screening test. 

• Examination Under Anesthesia

Anesthesia is required for corneal diameter measurement, tonometry, anterior chamber inspection with a hand-held slit light, fundoscopy, cycloplegic refraction, and documentation of all results.

• Ultrasound

It is used to determine the size of the tumor, to look for calcifications, and to rule out other illnesses such as Coats disease.

• Wide-Field Photography

Wide-field photography is utilized for analysis, documentation, and retinoblastoma care.

• CT SCAN 

CT scans help in the detection of calcifications, but due to radiation risks, it is avoided upon making the primary diagnosis.

• MRI 

MRI can be used to evaluate the optic nerve, extraocular extension, pineoblastoma, and to rule out other illnesses. 

• Systemic Assessment

Physical examination, MRI orbit and brain, bone scan, bone marrow aspiration, and lumbar puncture are all part of the procedure.

DNA analysis

Blood samples should be collected not just from the patient, but also from the patient's parents and any siblings for DNA analysis, which might assist in genetic counseling.

In the examination of the retinoblastoma gene, there are direct and indirect approaches. The direct technique seeks to identify the original mutation that caused the tumor to form; it is then evaluated if the mutation is present in the afflicted patient's germline. In circumstances when the original mutation cannot be found or its existence is questionable, indirect approaches can be employed.

The DNA to be tested directly comes from tumor cells or leukocytes. Retinoblastoma gene deletions or rearrangements can be discovered using karyotyping or Southern blotting methods.

Point mutations in the retinoblastoma gene can be identified by ribonuclease protection, denaturing gradient gel electrophoresis, single-strand conformation polymorphism, or direct DNA sequencing amplified by polymerase chain reaction.

Retinoblastomas can also be caused by hypermethylation of the retinoblastoma gene's promoter region, which deactivates the gene but does not change the DNA sequence. Southern blot analysis can also identify this. Indirect retinoblastoma gene analysis relies on DNA polymorphisms within this gene.

Management

Retinoblastoma is treated with a multidisciplinary team that includes an ophthalmologist, pediatric oncology, ocular pathologist, geneticist, allied health worker, and parents. The following therapeutic techniques are used to treat retinoblastoma:

CHEMOTHERAPY

The mainstay of treatment is CHEMOTHERAPY. It can also be used in conjunction with local therapy. Depending on the severity of the retinoblastoma, three to six rounds of intravenous carboplatin, etoposide, and vincristine are utilized. Single carboplatin or dual agent therapy, as well as bridging therapy to prevent harsh measures, can be employed in certain individuals and has demonstrated positive results. Although there is a minor risk of extraocular spread with intravitreal melphalan, it is utilized in situations with vitreous seeding. To optimize tumor control, chemotherapy is followed by cryotherapy or transpupillary thermal treatment.

• Transpupillary thermal therapy (TTT) is most commonly used for localized consolidation following chemotherapy, although it can also be utilized as a stand-alone treatment. TTT has an immediate impact, but it also enhances the effects of chemotherapy.

• CRYOTHERAPY: the triple freeze-thaw technique is an option for pre equatorial tumors without deeper invasion or vitreous seedings.

• BRACHYTHERAPY is used for an anterior tumor when there is no vitreous seeding and in cases of resistance to chemotherapy.

• When feasible, EXTERNAL BEAM RADIOTHERAPY is avoided, especially in the case of heritable retinoblastoma, because it might result in a second tumor. Although retinoblastomas are radiosensitive, side effects include cataract, radiation neuropathy, radiation retinopathy, and orbital hypoplasia.

• ENUCLEATION: Enucleation is performed when there is anterior chamber infiltration, neovascular glaucoma, optic nerve invasion, or if the tumor occupies more than half of the vitreous fluid. It is also helpful when chemotherapy has failed, as well as in cases with diffuse retinoblastoma, which has a poor visual prognosis and a high chance of recurrence. Enucleation should be performed with as little manipulation as possible, and a segment of the optic nerve measuring about 10 mm should be excised. Recent advancements in enucleation procedures now allow for the removal of a lengthy portion of the optic nerve while still under direct eyesight.

• EXTRAOCULAR EXTENSION When there is retrolaminar or extensive choroidal spread, 6 months of adjuvant chemotherapy is administered after enucleation. External beam radiation is utilized when the tumor extends up to the cut end of the optic nerve upon enucleation or through the sclera.

Differential Diagnosis

The differential diagnosis of retinoblastoma includes diseases such as:

• Persistent anterior fetal vasculature
• Persistent posterior fetal vasculature
• Coats disease
• Retinopathy of prematurity
• Toxocariasis
• Uveitis
• Vitreoretinal dysplasia
• Coloboma of the choroid and optic disk
• Posterior cataract

Staging

The newest retinoblastoma staging method is the International Classification for Intraocular Retinoblastoma. This staging approach categorizes intraocular retinoblastoma into five categories, A through E. Using available therapeutic techniques, A suggests a better prognosis while E implies a worse prognosis. The following is the staging:

• Group A: Small (3 mm in diameter) tumors that solely exist in the retina and are not located near critical structures such as the optic disc (where the optic nerve enters the retina) or the foveola (the center of vision)
• Group B: All other cancers that are still exclusively in the retina and are 3 mm in diameter or smaller but near to the optic disc or foveola.
• Group C: Tumors that are well-defined and have a little degree of dissemination under the retina (subretinal seeding) or into the jellylike substance that fills the eye (vitreous seeding)
• Group D: Tumors that are large or poorly defined, with extensive vitreous or subretinal seeding; the retina may have gotten detached from the back of the eye.
• Group E: The tumor is very big, reaches near the front of the eye, is bleeding or causing glaucoma (high pressure within the eye), or has other characteristics that indicate absolutely no chance of saving the eye.

Prognosis

Patients with intraocular retinoblastoma have a great prognosis and an overall survival rate of more than 95 percent in industrialized nations, particularly those who have access to contemporary health care facilities.

Extraocular extension, either through the sclera or by optic nerve invasion, is the most serious risk factor linked with a poor prognosis. Patients who survive bilateral retinoblastoma are more likely to have non-ocular malignancies later in life; the latent period for the formation of the second tumor is typically 9 months.

External beam radiation shortens the latent period and raises the chance of second cancer in the first 30 years of life. Sarcoma is the most common form of second malignancy. Patients with sarcoma have a less than 50% chance of survival.

On tests of verbal learning and short- and long-term verbal memory, patients with bilateral illness did much better than those with unilateral disease. Total brain radiation exposure was adversely connected with performance on tests of verbal learning and memory. Diagnosis at less than one year of age was associated with higher performance on a number of verbal domains.

Complications

If retinoblastoma is left untreated patient is likely to develop the following complications:

• Retinal detachment
• Retinal necrosis
• Orbital invasion
• Optic nerve invasion 
• Blindness 
• Intracranial extension
• Secondary neoplasms
• Metastasis
• Tumor recurrence
• Temporal bone hypoplasia
• Cataract
• Radiation neuropathy 
• Radiation retinopathy

Conclusion 

Retinoblastoma care is difficult and necessitates the collaboration of an ophthalmologist, pediatric oncology, ocular pathologist, geneticist, allied health providers, and parents. Almost always, the patient presents to the nurse practitioner or primary care provider first. Because this is an uncommon condition that requires quick attention, the patient should be sent to an ophthalmologist very once.

The cornerstone of long-term retinoblastoma management is rigorous adherence to the treatment plan, and diligent follow-up at regular intervals following treatment is necessary for early identification of recurrence or growth of a new tumor, particularly in individuals with hereditary illness.

Patients must be educated about their treatment options, which include chemotherapy, surgery, and radiation. Primary care clinicians should be conversant with these patients' postoperative care and when to refer them back to the ophthalmologist.

Because chemotherapy is the basis of treatment, the engagement of a pharmacist with oncologic treatment experience is critical. The pharmacist may confirm agent selection, dose, and medication reconciliation, as well as report any issues to the healthcare team. Because nursing is most likely in charge of providing the chemo, a strong relationship and open communication between pharmacy and nursing personnel are essential.

All patient management is best accomplished in conjunction with an expert ophthalmologist who can give appropriate assistance. The prognosis is favorable for individuals who follow the treatment plan and receive sufficient follow-up.

Retinoblastoma is a difficult diagnosis to manage, and as such, an interdisciplinary team approach is required, with doctors, specialists, specialty-trained nurses, and pharmacists all cooperating across disciplines to obtain the best possible patient outcomes.