Retinoblastoma – Causes, Symptoms, Diagnosis, Treatment

Retinoblastoma (Rb) 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 it is almost exclusively found in young children.^[rx]

Retinoblastoma is an uncommon type of malignancy occurring in 1 per 18000 childbirths, but it is the most commonly encountered primary intraocular malignancy of childhood and accounts for 3% cases of all childhood cancers.[rx] It is also the second most prevalent intraocular malignant tumor after uveal melanoma. In specialized care centers, survival rates are up to 95% with retention of vision in most cases, but it is lower in developing countries. Retinoblastoma is composed of retinoblasts (basophilic cells with hyperchromatic nuclei and scanty cytoplasm). Mostly retinoblastomas are undifferentiated, but different degrees of differentiation are present owing to the formation of structures known as rosettes. The tumor can be endophytic (in vitreous) and seeding of tumor cells throughout the eye, or it can be exophytic (in subretinal space), or it can demonstrate a mixed presentation. Optic nerve invasion can occur with the spread of tumor in subarachnoid space and into the brain. Metastatic spread occurs in regional lymph nodes, liver, lungs, bones, and brain.[rx]

Types of Retinoblastoma

Retinoblastoma is –

• Unilateral – if only one eye is affected by retinoblastoma. About 60% of affected individuals have unilateral retinoblastoma with a mean age at diagnosis of 24 months. Usually, in individuals with unilateral retinoblastoma the tumor is also unifocal (i.e., only a single tumor is present). Some individuals have multifocal tumors in one eye (unilateral multifocal retinoblastoma). Intraocular seeding may mimic primary multifocal tumor growth. In most persons with unilateral retinoblastoma without a family history, the tumor is large and it is not possible to determine if a single tumor is present.
• Bilateral – if both eyes are affected by retinoblastoma. About 40% of affected individuals have bilateral retinoblastoma with a mean age at diagnosis of 15 months. In most children with bilateral tumors, both eyes are affected at the time of initial diagnosis. In individuals with bilateral retinoblastoma, both eyes may show multiple tumors. Some children who are initially diagnosed with unilateral retinoblastoma later develop a tumor in the contralateral unaffected eye.
• Trilateral – if bilateral (or, rarely, unilateral) retinoblastoma and a pineoblastoma develop.

Causes of Retinoblastoma

Retinoblastoma occurs as a result of a mutation in the RB1 tumor suppressor gene located at the long arm of chromosome 13 at locus 14 (13q14).[rx] Formation of tumor occurs when both the copies of the RB1 gene are mutated. In the case of bilateral retinoblastoma, there are 98% chances that the mutation is germline. Only 5% of cases of retinoblastoma have a family history. 95%  of retinoblastoma cases are sporadic, of which 60 % of patients have unilateral disease with no associated germline mutation. Remaining patients present with germline mutations along with the development of multiple tumors.

• Heritable – In this type of retinoblastoma, there is a mutation in one of the alleles of the RB1 gene in all body cells. When the second allele has a mutation as a result of some mutagenic event, it leads to the malignant transformation of cells. Due to the presence of the mutation in all cells, a large number of these children develop bilateral and multifocal retinoblastoma. Heritable disease patients are at significant risk of nonocular cancers such as pineoblastoma, osteosarcoma, soft tissue sarcomas, and melanomas: these malignancies usually occur in a particular age group.[rx] The chances of second malignancy are 6%, but the risk increases five-fold when external beam radiation has been used to treat the primary tumor.
• Non-heritable – Non-heritable retinoblastomas are unilateral and are not transmitted. There is no risk of non-ocular cancers in these patients. In the case of unilateral retinoblastoma with no positive family history, it is non-heritable retinoblastoma, and the corresponding risk in each sibling and patient’s offspring is 1%. Almost 90% of unilateral retinoblastomas cases are of the nonhereditary form.

The risk to Family Members

Parents of a proband

• Some individuals diagnosed with heritable retinoblastoma inherited an RB1 pathogenic variant from a parent who may or may not be affected.
• In approximately 5% of probands with a heterozygous germline RB1 pathogenic variant who represent simplex cases (i.e., a single affected individual in the family), one of the proband’s unaffected parents also has the pathogenic variant. In most cases, this is a mosaic or heterozygous “reduced-penetrance” pathogenic variant, such as a missense variant.
• A proband with heritable retinoblastoma may have the disorder as the result of a de novo germline RB1 pathogenic variant. The majority of individuals with heritable retinoblastoma and no family history of retinoblastoma have the disorder as the result of a de novo pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant. If the RB1 pathogenic variant in the proband is not known, recommendations for the evaluation of parents of a proband include examination by an ophthalmologist knowledgeable about retinoblastoma, retina, and retinoblastoma-associated eye lesions.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. The incidence of parental mosaicism detected by MLPA or Sanger sequencing is >2% [Author, unpublished data]. With more sensitive methods such as allele-specific PCR or next-generation sequencing [Chen et al 2014], parental mosaicism is detected in >4% of families.
• The family history of some individuals diagnosed with heritable retinoblastoma may appear to be negative because of failure to recognize the disorder in family members (retina), low-level mosaicism, or reduced penetrance. Therefore, apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If the proband with retinoblastoma has the disorder as the result of a somatic mosaic RB1 pathogenic variant (i.e., a variant resulting from a mutation that occurs in the proband during embryonic development), the parents do not have the pathogenic variant.
• Note If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and have fewer (unilateral) or no retinoblastomas.

Sibs of a proband. The risk to sibs of a proband depends on the phenotype and the genetic status of the parents:

• The phenotype of the parents
  • If a parent of the proband and the proband have bilateral retinoblastoma, the risk to the sibs is 50%. In rare families with “familial low-penetrance retinoblastoma” the risk for tumor development in a sib with the germline pathogenic variant is reduced.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (i.e., 1%-2%. The sibs of a proband with clinically unaffected parents are still at increased risk for heritable retinoblastoma because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
• Genetic status of the parents
  • If a parent is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50% and testing of sibs for the RB1 pathogenic variant is warranted. In rare families with “familial low-penetrance retinoblastoma” the risk for tumor development in a sib with the germline pathogenic variant is reduced.
  • If the RB1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low (< 5%) but greater than that of the general population because of the possibility of parental germline mosaicism. Thus, it is still recommended that each sib be tested for the RB1 pathogenic variant identified in the proband; if the known familial RB1 pathogenic variant is not identified, the sib is “H0”.
• If the proband clearly shows mosaicism for an RB1 cancer-predisposing variant in non-cancer cells such as leukocyte DNA, it is assumed that the pathogenic variant arose as a postzygotic event and that neither parent has an RB1 germline pathogenic variant. The risk to the sibs is not increased and thus the testing of sibs for the RB1 pathogenic variant identified in the proband is not warranted.
• If molecular genetic testing – is not available or is uninformative, empiric risks based on tumor presentation (e.g., unifocal or multifocal) and family history can be used (Table 3) [Skalet et al 2018]. The low, but not negligible, risk to sibs of a proband with a negative family history presumably reflects the presence of either a germline RB1 pathogenic variant with reduced penetrance in one parent or somatic mosaicism (that includes the germline) for an RB1 pathogenic variant in one parent. If a parent has a cytogenetically detectable balanced chromosome 13 translocation or rearrangement, the sibs are at increased risk of inheriting an unbalanced chromosome rearrangement.

Off spring of a proband – Each child of an individual with heritable retinoblastoma has a 50% chance of inheriting the RB1 pathogenic variant.

• If the proband has bilateral retinoblastoma and no family history of retinoblastoma, the presence of a germline RB1 cancer-predisposing variant is assumed (H1) and the risk to each offspring of inheriting the pathogenic variant is 50%. Predictive DNA testing in offspring is possible if the cancer-predisposing RB1 variant has been identified in the proband.
• If the proband has had unilateral multifocal retinoblastoma and no family history of retinoblastoma, recurrence risk to offspring is lower.
• The risk to offspring of a proband with unilateral unifocal disease and negative family history is 6%, reflecting the possibility that the proband has mosaicism for a pathogenic variant or a germline RB1 pathogenic variant associated with milder phenotypic expression. In families with “familial low-penetrance retinoblastoma” the risk for tumor development in persons with the low-penetrance RB1 allele is lower than the 95% observed with highly penetrant RB1 “null” alleles.
• If the RB1 pathogenic variants that have been detected in tumor tissue are not detected in DNA from leukocytes of the proband, there is an estimated 1.2% chance that the proband has germline mosaicism for one of the pathogenic variants identified in the tumor tissue. The offspring of the proband are at a 0.6% risk of inheriting a germline pathogenic variant [Richter et al 2003]. Molecular genetic testing in offspring will check for both of the pathogenic variants identified in the tumor of the proband.
• If one of the pathogenic variants identified in the tumor is mosaic in DNA from leukocytes of the proband, the level of germline involvement is uncertain. All offspring should be checked for the pathogenic variant identified in leukocyte DNA.

Symptoms of Retinoblastoma

• Intraretinal tumor – Intraretinal retinoblastoma is homogenous, dome-shaped whitish lesion along 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 a retinal detachment.
• White color in the center circle of the eye (pupil) – when light is shone in the eye, such as when taking a flash photograph
• Eyes that appear to be looking in different directions
• Eye redness
• Eye swelling
• an unusual white reflection in the pupil – it often looks like a cat’s eye that’s reflecting light and may be apparent in photos where only the healthy eye appears red from the flash, or you may notice it in a dark or artificially lit room
• a squint
• a change in the colour of the iris – in 1 eye or sometimes only in 1 area of the eye
• a red or inflamed eye – although your child will not usually complain of any pain
• poor vision – your child may not focus on faces or objects, or they may not be able to control their eye movements (this is more common when both eyes are affected); they may say they cannot see as well as they used to

Signs in older children include the eye appearing red, sore or swollen, and some loss of vision in the affected eye.

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

Diagnosis of Retinoblastoma

History and Physical

Patients with retinoblastoma present mostly within the first year of age in the case of bilateral disease and within 3 years of age in case of unilateral disease. It is important to ask about a family history of ocular malignancies. The most common presenting features are the following:

• Eye examination – Intraocular retinoblastoma is usually diagnosed without pathologic confirmation. An examination under anesthesia with a maximally dilated pupil and scleral indentation is required to examine the entire retina. Very detailed documentation of the number, location, and size of tumors; the presence of retinal detachment and subretinal fluid; and the presence of subretinal and vitreous seeds must be performed.
• Leucovorin – (whitish pupillary reflex): It is the most common presenting feature and accounts for 60% of cases.
• Strabismus – It is the second common presenting feature, and it is therefore important to perform fundus examination in all patients of childhood squint.
• Painful red eye – Painful red along with secondary glaucoma and associated buphthalmos can be present.
• Inflammation – Orbital inflammation resembling pre-septal or orbital cellulitis can also be a presenting feature.
• Metastatic disease – Metastatic disease involving lymph nodes, liver, lungs, brain, and bones is rare before ocular involvement.
• Visible extraocular growth
• Decreased vision
• Restriction of extraocular movements

Evaluation

• Ocular ultrasound and magnetic resonance imaging (MRI) – Bidimensional ocular ultrasound and MRI can be useful to differentiate retinoblastoma from other causes of leukocoria and in the evaluation of extrascleral and extraocular extension in children with advanced intraocular retinoblastoma. Optic nerve enhancement by MRI does not necessarily indicate involvement; cautious interpretation of those findings is needed.[rx]
• Reverse transcriptase-polymerase chain reaction (RT-PCR) – The detection of the synthetase of ganglioside GD2 mRNA by RT-PCR in the cerebrospinal fluid at the time of diagnosis may be a marker for CNS disease.[rx]
• Direct Ophthalmoscopy – Red reflex testing with a direct ophthalmoscope is the simplest test, and leukocoria is easily observable. This method serves as a simple screening test.[rx]
• Examination Under Anesthesia – Examination under anesthesia is necessary for measuring the corneal diameter, for tonometry, anterior chamber examination with a hand-held slit lamp, fundoscopy, cycloplegic refraction, and documenting all findings.
• Ultrasound – To assess the size of the tumor, to observe calcifications, and it also helps to rule out similar conditions like coats disease.
• Wide-Field Photography – Wide-field photography is used for analysis, documentation, and helps in the management of retinoblastoma.
• 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 is useful in the evaluation of optic nerve, extraocular extension, pineoblastoma, and to exclude similar diseases.[rx]
• Systemic Assessment – This includes a physical examination, MRI orbit and brain, bone scan, bone marrow aspiration, and lumbar puncture.
• Genetic Studies – Genetic studies of blood samples and tumor tissue from patients and relatives.[rx][rx]
• An eye exam with dilated pupil – An exam of the eye in which the pupil is dilated (opened wider) with medicated eye drops to allow the doctor to look through the lens and pupil to the retina. The inside of the eye, including the retina and the optic nerve, is examined with a light. In young children, this exam may be done under anesthesia.
  There are several types of eye exams that are done with the pupil dilated:

  • Ophthalmoscopy – An exam of the inside of the back of the eye to check the retina and optic nerve using a small magnifying lens and a light.
  • Fluorescein angiography – A procedure to look at blood vessels and the flow of blood inside the eye. An orange fluorescent dye called fluorescein is injected into a blood vessel in the arm and goes into the bloodstream. As the dye travels through blood vessels of the eye, a special camera takes pictures of the retina and choroid to find any blood vessels that are blocked or leaking.
• RB1 gene test – A laboratory test in which a sample of blood or tissue is tested for a change in the RB1 gene.
• Ultrasound exam of the eye – A procedure in which high-energy sound waves (ultrasound) are bounced off the internal tissues of the eye to make echoes. Eye drops are used to numb the eye and a small probe that sends and receives sound waves is placed gently on the surface of the eye. The echoes make a picture of the inside of the eye and the distance from the cornea to the retina is measured. The picture, called a sonogram, shows on the screen of the ultrasound monitor. The picture can be printed to be looked at later.
• Bone scan – A procedure to check if there are rapidly dividing cells, such as cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones with cancer and is detected by a scanner that also takes a picture of the body. Areas of bone with cancer show up brighter in the picture because they take up more radioactive material than normal bone cells do.
• Bone marrow aspiration and biopsy – The removal of bone marrow and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow under a microscope to look for signs of cancer. A bone marrow aspiration and biopsy are done if the doctor thinks cancer has spread outside of the eye.
• Lumbar puncture – A procedure used to collect cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle between two bones in the spine and into the CSF around the spinal cord and removing a sample of the fluid. The sample of CSF is checked under a microscope for signs that cancer has spread to the brain and spinal cord and sometimes it is also checked for a tumor marker called ganglioside GD2. This procedure is also called an LP or spinal tap.

Treatment of Retinoblastoma

Treatment of retinoblastoma involves a multidisciplinary approach involving an ophthalmologist,  pediatric oncologist, ocular pathologist, geneticist, allied health professional, and parents. Different treatment modalities employed in the treatment of retinoblastoma are;

• There are different types of chemotherapy

  • Systemic chemotherapy –  When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body. Systemic chemotherapy is given to shrink the tumor (chemo reduction) and avoid surgery to remove the eye. After chemo reduction, other treatments may include radiation therapy, cryotherapy, laser therapy, or regional chemotherapy. However, extra orbital disease requires intensive chemotherapy and may include consolidation with high-dose chemotherapy and autologous stem cell transplantation with or without radiation therapy.
    Systemic chemotherapy may also be given to kill any cancer cells that are left after the initial treatment or to kill cancer cells that are outside the eye. Treatment given after the initial treatment, to lower the risk that cancer will come back, is called adjuvant therapy.
  • Regional chemotherapy – When chemotherapy is placed directly into the cerebrospinal fluid (intrathecal chemotherapy), an organ (such as the eye), or a body cavity, the drugs mainly affect cancer cells in those areas. Several types of regional chemotherapy are used to treat retinoblastoma.
  • Ophthalmic artery infusion chemotherapy – Ophthalmic artery infusion chemotherapy carries anticancer drugs directly to the eye. A catheter is put into an artery that leads to the eye and the anticancer drug is given through the catheter. After the drug is given, a small balloon may be inserted into the artery to block it and keep most of the anticancer drug trapped near the tumor. This type of chemotherapy may be given as the initial treatment when the tumor is in the eye only or when the tumor has not responded to other types of treatment. Ophthalmic artery infusion chemotherapy is given at special retinoblastoma treatment centers.
  • Intravitreal chemotherapy – Intravitreal chemotherapy is the injection of anticancer drugs directly into the vitreous humor (jelly-like substance) inside of the eye. It is used to treat cancer that has spread to the vitreous humor and has not responded to treatment or has come back after treatment.
  • Intrathecal chemotherapy – Intrathecal chemotherapy is the injection of anticancer drugs directly into the cerebrospinal fluid (CSF). It is used to treat cancer that has spread to the brain.
  • Chemotherapy – Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. The way the chemotherapy is given depends on the stage of cancer and where the cancer is in the body.
• Radiation therapy

  Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy

  • External-beam radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.
    Certain ways of giving radiation therapy can help keep radiation from damaging nearby healthy tissue. These types of radiation therapy include the following:

    –Intensity-modulated radiation therapy (IMRT) – IMRT is a type of 3-dimensional (3-D) external radiation therapy that uses a computer to take pictures of the size and shape of the tumor. Thin beams of radiation of different intensities (strengths) are aimed at the tumor from many angles.

    –Proton-beam radiation therapy – Proton-beam therapy is a type of high-energy, external radiation therapy. A radiation therapy machine aims streams of protons (tiny, invisible, positively-charged particles) at the cancer cells to kill them.

  • Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near cancer. Certain ways of giving radiation therapy can help keep radiation from damaging nearby healthy tissue. This type of internal radiation therapy may include the following:

    –Plaque radiotherapy – Radioactive seeds are attached to one side of a disk, called a plaque, and placed directly on the outside wall of the eye near the tumor. The side of the plaque with the seeds on it faces the eyeball, aiming radiation at the tumor. The plaque helps protect other nearby tissue from the radiation.

  Whether internal or external radiation therapy is given depends on the stage of the cancer being treated, where it is found in the body, and how cancer responded to other treatments.

• TTT (Transpupillary thermal therapy) – is used mostly for focal consolidation after chemotherapy; however, it can be used as an isolated treatment. TTT has a direct effect but also augments the effects of chemotherapy.
• Cryotherapy – Cryotherapy is based on the application of a cryoprobe to the sclera in the immediate vicinity of the retinal tumor. Cryotherapy is used as primary therapy or with chemotherapy for tumors smaller than 4 disc diameters (DD) in the anterior portion of the retina.
• Laser therapy – Laser therapy may be used as primary therapy for small tumors or in combination with chemotherapy for larger tumors. Traditional photocoagulation (argon laser), in which the laser was applied around the tumor to targeting the tumor vasculature, has given way to thermotherapy (diode laser). Thermotherapy is delivered directly to the tumor surface via infrared wavelengths of light.[rx,rx]
• Brachytherapy (plaque radiation therapy) – For larger tumors that are not amenable to cryotherapy or laser therapy, brachytherapy can provide an effective means for local control (refer to the Radiation Therapy section of this summary for more information). It is used for an anterior tumor when there is no vitreous seeding and in cases of resistance to chemotherapy.
• External beam radiotherapy- is avoided when possible, especially in the case of heritable retinoblastoma because it can result in a second malignancy. Retinoblastomas are radiosensitive, but adverse effects include cataract, radiation neuropathy, radiation retinopathy, and hypoplasia of orbit.[rx]
• Thermotherapy – Thermotherapy is the use of heat to destroy cancer cells. Thermotherapy may be given using a laser beam aimed through the dilated pupil or onto the outside of the eyeball. Thermotherapy may be used alone for small tumors or combined with chemotherapy for larger tumors. This treatment is a type of laser therapy.
• Enucleation – enucleation is performed when there is the infiltration of the anterior chamber, neovascular glaucoma, invasion of the optic nerve, and if the tumor comprises more than half of the vitreous volume. It is also useful when chemotherapy has failed and in cases of diffuse retinoblastoma due to poor visual prognosis and a high risk of recurrence. Minimal manipulation should take place when performing enucleation, and a portion of the optic nerve of about 10 mm requires excision.[rx] Recent advances in enucleation techniques now allow the removal of a long segment of the optic nerve under direct vision.[rx]
• Extraocular extension – Adjuvant chemotherapy for 6 months is given following enucleation when there is retrolaminar or massive choroidal spread. When the extension of the tumor is up to the cut end of the optic nerve at enucleation, or it is through the sclera, then external beam radiation is used.
• Laser photocoagulation – Laser photocoagulation is used for small posterior tumors 4 mm in basal diameter and 2 mm in thickness.[rx,rx] The treatment is directed to delimit the tumor and coagulate the blood supply to the tumor by surrounding it with two rows of overlapping laser burns. Complications include transient serous retinal detachment, retinal vascular occlusion, retinal hole, retinal traction, and preretinal fibrosis. It is less often employed now with the advent of thermotherapy. In fact, laser photocoagulation is contraindicated while the patient is on an active chemo reduction protocol.[rx]
• Plaque brachytherapy – Plaque brachytherapy involves the placement of a radioactive implant on the sclera corresponding to the base of the tumor to trans-scleral irradiation of the tumor.[rx] Commonly used radioactive materials include Ruthenium 106 and Iodine 125. The advantages of plaque brachytherapy are focal delivery of radiation with minimal damage to the surrounding normal structures, minimal periorbital tissue damage, absence of cosmetic abnormality because of retarded bone growth in the field of irradiation as it occurs with external beam radiotherapy, reduced risk of second malignant neoplasm and shorter duration of treatment. Plaque brachytherapy requires precise tumor localization and measurement of its basal dimensions. The tumor thickness is measured by ultrasonography. The data are used for dosimetry on a three-dimensional computerized tumor modeling system. The plaque design is chosen depending on the basal tumor dimensions, its location, and configuration. The dose to the tumor apex ranges from 4000 to 5000 cGy. The plaque is sutured to the sclera after confirming tumor centration and is left in situ for the duration of exposure, generally ranging from 36 to 72 h. The common complications are radiation papillopathy and radiation retinopathy.[rx]
• External beam radiotherapy – External beam radiotherapy was the preferred form of management of moderately advanced retinoblastoma in the late 1900s.[rx,rx] Presently it is indicated in eyes where primary chemotherapy and local therapy had failed, or rarely when chemotherapy is contraindicated.[rx]
• Enucleation – Primary enucleation continues to be the treatment of choice for advanced intraocular retinoblastoma with neovascularization of iris, secondary glaucoma, anterior chamber tumor invasion, tumors occupying >75% of the vitreous volume, necrotic tumors with secondary orbital inflammation, and tumors associated with hyphema or vitreous hemorrhage where the tumor characteristics cannot be visualized, especially when only one eye is involved.[rx]
• Intra-arterial chemotherapy – Chemotherapeutic drugs are administered locally by a thin catheter threaded through the groin, through the aorta, and the neck, directly into the optic vessels.^[rx]
• Nanoparticulate chemotherapy – To reduce the adverse effects of systemic therapy, subconjunctival (local) injection of nanoparticle carriers containing chemotherapeutic agents (carboplatin) has been developed, which has shown promising results in the treatment of retinoblastoma in animal models without adverse effects.^[rx][rx]
• Chemoreduction – is a combined approach using chemotherapy to initially reduce the size of the tumor, and adjuvant focal treatments, such as transpupillary thermotherapy, to control the tumor.^[rx][rx]

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

References