Retinoblastoma

Essential Information

Summarize

Retinoblastoma (RB) is the most common intraocular malignancy in children and is caused by mutations or deletions in the tumor suppressor gene RB1. It is inherited in approximately 40% of cases and is autosomal dominant. More than half of the children with retinoblastoma have white pupils, commonly known as "cat's eyes", which are yellowish-white reflections in the pupil area. About 20% of the children with retinoblastoma have strabismus, and other possible symptoms may include low vision, redness of the eyes, eye distention, eye pain, swelling of the eyelids, and protrusion of the eyeballs.
The treatment of retinoblastoma is life-saving, followed by eye-saving treatment (intravenous chemotherapy, ophthalmic artery interventional chemotherapy, and topical treatment) or surgery (eye removal, orbital enucleation, etc.), depending on the condition of the disease. Retinoblastoma is one of the best-treated malignancies, with a five-year survival rate for intraocular stage tumors of more than 90%. However, some children may lose their vision or require eye removal.

Epidemiological

incidence of a disease

Retinoblastoma is mostly found in children, especially those under 3 years old. The incidence rate is about 1:18,000 ~ 1:21,000, and the number of new patients in China is about 1,100 per year, most of which are advanced and high-risk patients. About 90% of children develop the disease before the age of 3. 70%-80% of children develop the disease in one eye and 20%-30% develop the disease in both eyes. Adult onset is rare. There are no regional, racial or gender differences.

Etiolog & Risk factors

risk factor

Retinoblastoma is divided into hereditary and non-hereditary types, which are intraocular malignant tumors caused by mutation or deletion of the tumor suppressor gene RB1.
The hereditary type accounts for about 40% of retinoblastomas, and is caused by mutations in the germ cells of children whose parents are carriers of the mutated gene, or whose parents are normal, and is inherited in an autosomal dominant manner. About 10-15% of children have a clear family history of retinoblastoma.
The nongenetic type accounts for about 60% of retinoblastomas and is caused by genetic mutations.
There are no clear predisposing factors for this disease.

Classification & Stage

Currently, there are two systems used internationally for neuroblastoma staging: the International Neuroblastoma Risk Group (INRG) staging system and the International Neuroblastoma Staging System (INSS).The INRG staging is a pre-treatment staging system based on Imaging Risk Factors (IDRFs); while the INSS is a postoperative staging system based on surgical situation and pathology.

Typing according to pathogenesis

Based on the pathogenesis, they are categorized into genetic and non-genetic types.
Hereditary type
The onset of disease is usually before the age of 1 year, most often in both eyes, and the suprachoroidal tumors are multifocal, predisposing to the development of primary second tumors at other sites.
Non-hereditary type
The onset of the disease is later, most often monocular, and the retinal tumor is multifocal, and is prone to develop primary second tumors at other sites.

Typing according to site of onset

Depending on the site of development, retinoblastoma can be categorized as unilateral, bilateral and trilateral retinoblastoma.
Unilateral retinoblastoma
Only one eye is affected.
Bilateral retinoblastoma
It develops in both eyes, either simultaneously or sequentially.
Trilateral retinoblastoma
Bilateral retinoblastoma with intracranial primary neuroblastoma of the pineal gland or pterygoid region.

Staging according to tumor progression

Depending on the extent of tumor progression, it can be divided into intraocular and extraocular stages.
Intraocular stage
The tumor is confined within the eyeball and may invade the choroid, ciliary body, anterior chamber, and optic nerve papilla, but does not invade the periocular area or other tissues of the body.
Extraocular stage
The tumor has infiltrated tissues outside the eye and may metastasize to the central nervous system, bone marrow, or lymph nodes.

International Staging of Retinoblastoma (IIRC)

For intraocular stage retinoblastoma, it is generally staged using the International Staging of Retinoblastoma (IIRC).
Stage A
Small intraretinal tumors distant from the central macular recess and optic disc. All tumors have a maximum diameter of <3 mm; all tumors are >3 mm from the macular central recess and >1.5 mm from the optic disc.
Stage B
Intraretinal tumors without size and location limitations based on stage A; tumors without vitreous or subretinal implants.
Stage C
Tumor with minor subretinal or vitreous implantation. One or more scattered tumors with limited subretinal implantation within 3 mm of the tumor margin, or limited tiny vitreous implantation adjacent to a single tumor with subretinal fluid 3 mm beyond the tumor margin.
Stage D
Diffuse lesion with significant vitreous cavity or subretinal implantation. One or more large, diffusely distributed tumors with lamellar subretinal implantation, diffuse vitreous cavity implantation, and large amounts of subretinal fluid causing total retinal detachment.
Stage E
Extensive tumor growth, destruction of ocular structure and loss of function. Specific manifestations include: tumor contacting the lens; neovascular glaucoma; anterior tumor reaching the anterior vitreous surface, involving the ciliary body or the anterior chamber of the eye; massive intraocular hemorrhage; necrosis of the tumor with aseptic orbital cellulitis; ocular atrophy; and suspicious optic nerve and/or ocular wall involvement on imaging.

TNM staging

Based on the volume and location of the primary tumor, as well as regional lymph nodes and distant metastases, the 8th edition of the Cancer Staging Manual issued by the American Joint Committee of Cancer (AJCC) in 2017 proposes the latest TNM staging for retinoblastoma, and TNM staging allows for a more comprehensive assessment of the tumor.
Primary tumor (T)
cTx stage
Tumor cannot be evaluated
cT0
No evidence of tumor presence
cTl stage
Intraretinal tumor, distance between tumor base and subretinal fluid ≤ 5.0 mm
● Stage cTla
Tumor diameter ≤ 3.0 mm and distance from macula and optic disc > 1.5 mm
● cTlb stage
Tumor diameter > 3.0 mm or distance from macula and optic disc < 1.5 mm
cT2 stage
Intraocular tumor with retinal detachment, vitreous implantation or subretinal implantation
● Stage cT2a
Distance between the subretinal fluid and the base of the tumor > 5.0 mm
● Stage cT2b
Tumor with vitreous implant or subretinal implant
Stage cT3
Progressive intraocular tumor
● Stage cT3a
Atrophy of the eyeball
● cT3b stage
Tumor invades ciliary flats, ciliary body, lens, suspensory ligament, iris or anterior chamber
● Stage cT3c
Elevated intraocular pressure with iris neovascularization and/or bull's eye
● Stage cT3d
Anterior chamber hemorrhage and/or massive vitreous hemorrhage
● Stage cT3e
Aseptic orbital cellulitis
Stage cT4
Extraocular stage tumor invading the orbit, including the optic nerve
● Stage cT4a
Imaging evidence of retrobulbar optic nerve involvement or optic nerve thickening, orbital tissue involvement
● Stage cT4b
Clinical examination reveals obvious eyeball protrusion and/or intraorbital masses
Localized lymph node metastasis (regional lymph node, N)
Stage cNx
Regional lymph node status cannot be assessed
Stage cN0
No lymph node metastasis found
cNl stage
Localized lymph node metastasis
Distant metastasis (metastasis, M)
cM0 stage
No symptoms of intracranial or distant metastasis
cMl stage
Distant metastasis without histopathologic confirmation
● cMla stage
Tumor metastasis to distant sites (bone marrow, liver, etc.) based on clinical or imaging studies
● cMlb stage
Imaging findings suggesting tumor metastasis to CNS but not trilateral RB
pM stage 1
Distant metastasis with histopathologic evidence
● pM l a stage
Histopathologic evidence of tumor metastasis to distant sites (bone marrow, liver, or other)
● pM lb stage
Histopathologic evidence of tumor metastasis to cerebrospinal fluid or central nervous system

Clinical manifestations

Retinoblastoma is difficult to detect in the early stages. When the tumor gradually increases in size, most children present with a yellowish-white reflection in the pupil area, known as albinism. Strabismus occurs in about 20% of children. Other possible symptoms include loss of vision, redness of the eyes, eye swelling, eye pain, eyelid swelling, and protruding eyeballs.

albinism

This is a yellowish-white reflection in the pupil area. The likelihood of detecting this symptom is related to the size of the pupil, and it is easier to detect when the pupil is naturally dilated in low light (e.g., when taking a picture of the child with a flash).
It is important to note that if you want to take a picture to self-check whether your child has white pupils, you must meet several conditions for taking the picture: 1. don't take the picture in a bright environment; 2. turn on the flash; 3. let your child look directly at the camera (the angle of the picture may also cause pupil reflections, so make sure to let your child look directly at the camera); 4. turn off the cell phone's "red-eye reduction" function. Turn off the "red-eye" function on your cell phone.

sideways glance

Strabismus occurs in about 20% of affected children. Generally, if there is a smaller retinoblastoma growing in or around the central retinal recess, it can cause a significant reduction in vision, which can result in the development of strabismus in the affected eye.

Other performance

This includes varying degrees of ocular redness and eye pain, corneal clouding, glaucoma, protruding eyeballs, and, in rare cases, redness and swelling of the eyelids and aseptic orbital cellulitis.
If funduscopic examination is performed, a grayish-white, round or oval, solid retinal mass with indistinct borders may be found, which may grow flattened along the choroidal surface or protrude into the vitreous cavity. Retinal blood vessels on the surface of the mass are dilated and hemorrhagic, and may be accompanied by exudative retinal detachment. Retinal masses can be single, multiple, or spread throughout the retina.
When the tumor penetrates the retina and enters the vitreous cavity and anterior chamber, it may cause vitreous clouding and pseudo anterior chamber pus, or it may form a grayish-white tumor nodule on the surface of the iris; when the tumor penetrates the sclera and invades the extraocular and intraorbital areas, it may cause a mass on the surface of the eye or protrusion of the eyeball.

Examination & Diagnosis

diagnostic strategy

Retinoblastoma needs to be detected and diagnosed early. Funduscopic examination is recommended to rule out retinoblastoma in infants up to 6 months of age who have strabismus. When taking a picture of your child with a flash, watch for yellowish-white reflections in the pupil area (albinism) (the angle at which the picture is taken may also cause pupil reflections, so be sure to have your child look directly into the lens), and once detected, consult the ophthalmology department of an ophthalmology hospital or general hospital as soon as possible.
If there is a family history of retinoblastoma, screening is needed after the child is born for early detection and diagnosis.
The diagnosis can usually be confirmed on the basis of family history, age of the child, signs and symptoms, and ancillary investigations. CT and magnetic resonance imaging (MRI) examinations are helpful in determining whether extraocular spread and metastasis of the tumor have occurred.

Retcam check

After dilating the pupils, an eye examination with Retcam is recommended to detect the specifics of fundus lesions, and the Retcam examination is extremely important in the diagnosis and follow-up of retinoblastoma.

Ultrasound examination of the eye

In the vast majority of cases, retinal tumors can be found to be solidly occupied and may show calcified images of the tumor, as well as the state of retinal involvement.

CT scan

In the vast majority of cases, a dense intraocular mass and intraocular calcified spots can be detected, and CT examination can reveal the presence of orbital bone involvement.CT examination can be qualitatively diagnostic of retinoblastoma in the majority of cases.

MRI examination

It has significantly higher resolution than CT for the examination of soft tissue lesions and is more accurate than CT in the evaluation of the optic nerve, orbital metastases, and in the detection of pineal tumors. MRI of the head and orbit can also evaluate trilateral retinoblastoma.

pathological examination

Pathologic examination is the gold standard for confirming the diagnosis of retinoblastoma. Intraocular puncture is usually not recommended to avoid spreading and metastasis of tumor cells. Retinoblastoma is visualized as single or multiple white masses in the retina. Microscopically, the tumor cells are small in size, with more cytoplasm and blue HE staining. Tumor cells show a spoke-like arrangement, like a chrysanthemum, i.e. retinoblastoma chrysanthemum cluster.

differential diagnosis

It needs to be differentiated from the following other eye diseases that can cause white pupil syndrome.

Coats disease
Coats disease occurs in male adolescents, usually in one eye, and is characterized by abnormal retinal vasodilatation, large yellowish-white lipid exudates and cholesterol crystals in and under the retina, and may be associated with exudative retinal detachment, usually without calcification.

Retinopathy of prematurity (ROP)
The child has a history of preterm labor, low body weight, and a history of high oxygen intake. Ischemia and hypoxia due to peripheral retinal underdevelopment results in proliferative lesions in both eyes, and in severe cases, tensor retinal detachment and white pupil syndrome when proliferative lesions constrict to the lens.
Permanent Primary Hyperplasia Vitreous (PHPV)
Permanent Primary Vitreous Hyperplasia (PHPV) is a congenital ocular anomaly that occurs at birth and is the result of undegenerated primitive vitreous bodies that proliferate behind the lens. It often develops monocularly, in term infants, is recognized at birth, and can present as a white pupil; however, ultrasound and CT do not show a solid occupying lesion.
Congenital cataract
Congenital cataract is a congenital disease that presents with a cloudy lens and a white pupil area; no solid space-occupying lesions are seen in the eye on ultrasound and CT scan.
Endophthalmitis
Endophthalmitis often occurs in children after a high fever, when pathogens reach the eye through the blood circulation. There is a large amount of exudate in the anterior chamber and vitreous humor of the affected eye, forming a vitreous abscess, and the pupil area appears yellowish-white, i.e., albinism, but the intraocular pressure of the affected eye is mostly lower than normal.
Other diseases that need to be differentiated
Other diseases that need to be differentiated include familial exudative vitreoretinopathy, vitreous parasites, corneal leukoplakia, retinal ventricular meningiomas, and ciliary body medullary epitheliomas.

Clinical Management

The principles of retinoblastoma treatment are: firstly, to save the life of the child, secondly, to consider the preservation of the affected eye, and thirdly, to consider the preservation of vision.
Depending on the size, location and degree of development of the tumor, different individualized treatment plans are used.
Currently, for intraocular stage retinoblastoma, the first line of therapy is chemotherapy (i.e., chemotherapy), including intravenous chemotherapy, arterial chemotherapy and vitreous cavity injection chemotherapy. Other treatments include topical ophthalmic treatments (laser photocoagulation, cryotherapy, transpupillary warming, etc.) and surgical treatments (enucleation of the eyeball, enucleation of the orbital contents, etc.).

chemotherapy

Intravenous Chemotherapy
A VEC regimen combining carboplatin (Carboplatin), vincristine (Vincristin), and etoposide (Etoposide) is generally used for treatment.
Arterial Chemotherapy
Arterial chemotherapy, also known as interventional chemotherapy, involves direct infusion of the chemotherapeutic drugs marfan, carboplatin, and topotecan into the eye through a femoral artery cannula from the internal carotid artery to the ophthalmic artery. The advantages are high local drug concentration in the tumor, strong killing effect and few side effects.
Vitreous Chemotherapy
It refers to the direct injection of chemotherapeutic drugs such as Marfan and Topotecan into the vitreous cavity. This treatment method is suitable for patients with vitreous tumor dissemination and implantation.

local treatment

Laser photocoagulation
This method is applicable to smaller tumors after the equatorial part. The mechanism of action is to use the thermal coagulation effect of laser to kill tumor cells directly. There are three laser wavelengths used in the clinic, namely, 532, 810 and 1064 nm, and the laser photocoagulation covers the tumor under the direct vision of the indirect ophthalmoscope.
Coagulation Therapy
It is used to treat small tumors in the equatorial region and its anterior part. The condensation source is carbon dioxide at -80°C.

surgical treatment

Eye removal
It is mainly used for patients with stage D and E retinoblastoma who have failed eye-preserving treatment. Surgical resection of the optic nerve is as long as possible to prevent tumor residue in the stump, which may affect the prognosis.
Orbital enucleation
It is used in cases where the tumor tissue has already penetrated the eyeball and grown into the orbit, and the optic nerve is thickened. Postoperative chemotherapy is required, and local radiation therapy can be performed if necessary. For huge intraorbital metastases, chemotherapy can be given to reduce the volume of the tumor first, and then orbital content enucleation can be performed.

radiotherapy

Radiation therapy is a treatment that uses radiation to stop the growth of tumor cells and kill them. Radiation therapy treatments that can be used to treat retinoblastoma include intensity-modulated radiation therapy (IMRT), proton radiation therapy, and plasmapheresis, in addition to conventional radiation therapy. The choice of radiation therapy depends on the patient's specific condition.

Treatment options for retinoblastoma

Treatment options for IIRC Stage A
Laser photocoagulation or condensation.
Treatment options for IIRC stage B
If the distance between the tumor and the macula is >3.0 mm and the distance from the optic disc is >1.5 mm, then laser photocoagulation or condensation is used, and intravenous chemotherapy is used if necessary.
If the distance between the tumor and the macula is ≤3.0 mm or the distance from the optic disc is ≤1.5 mm, intravenous chemotherapy is used, supplemented by laser photocoagulation or condensation.
Treatment options for IIRC stage C
Intravenous chemotherapy or arterial chemotherapy + laser photocoagulation, condensation or vitreous chemotherapy.
Treatment options for IIRC stage D
Intravenous chemotherapy or arterial chemotherapy + laser photocoagulation, coagulation or vitreous chamber chemotherapy, and if necessary, ocular extraction combined with one-stage ocular table implantation.
Treatment options for IIRC stage E
For those who fail to receive eye preservation treatment, ocular removal combined with one-stage ocular table implantation is usually required, and the postoperative administration of intravenous chemotherapy will be decided according to the pathologic and histologic conditions.
If there is no sign of extraocular metastasis of the tumor, one-stage ocular table implantation is usually performed after eye removal to improve the quality of patient's survival.
If the tumor has extended throughout the body, surgery for the ocular lesion (removal of the eyeball or enucleation of the orbital contents, etc.) is required, along with systemic chemotherapy and, if necessary, local radiation therapy to the orbit. If the tumor has metastasized to the central nervous system, radiotherapy to the brain and spinal cord areas is indicated in addition to chemotherapy.
Treatment of trilateral retinoblastoma
Surgery (removal of the eyeball or orbital contents, and removal of intracranial tumors) combined with intense chemotherapy and, in some cases, radiation therapy is required.

Prognosis

The prognosis of retinoblastoma depends on the clinical stage of the tumor, pathological staging, duration of the disease, etc. The time and method of treatment are also important factors affecting the prognosis of retinoblastoma. Early detection and early treatment are important prerequisites for improving the prognosis of retinoblastoma patients.
Retinoblastoma is one of the malignant tumors with the highest cure rate and has a better prognosis overall. The five-year survival rate for intraocular stage tumors exceeds 90%. With treatment most stage D and a few stage E patients are able to preserve their eyes.
After patients are discharged from the hospital, they need to be followed up regularly. The treatment plan is modified according to the results of the follow-up, changes in the condition, and the individual's recovery.

Routine

Home care

Apply eye drops and eye ointment as prescribed by the doctor, be careful about the frequency and do not forget. Do not allow the child to rub the treated eye as much as possible to avoid infection. After discharge from the hospital, the child should rest and avoid overexertion of the eyes.
If the child's eye is removed, a suitable prosthetic eye piece can be ordered for the child 1 month after surgery.

Management of daily life

Eat more fresh vegetables, etc., meat and vegetables to supplement vitamins, enhance physical fitness, pay attention to rest.

Daily disease monitoring

Funduscopic examination should be performed every 1 to 3 months after the tumor is stable; funduscopic examination should be performed every 3 to 6 months after 2 years of stability until adulthood.
After eye removal surgery, if there are no retinoblastoma risk factors, orbital MRI should be performed annually, and then follow the doctor's advice after 2 years according to their own recovery; if there are retinoblastoma risk factors, orbital MRI should be performed every 6 months after systemic chemotherapy, and then changed to yearly MRI after 2 years until adulthood. Lifelong follow-up of patients with retinoblastoma is indicated.

Special Notes

In the event of tumor recurrence or the appearance of a new tumor lesion, treatment will need to be repeated. If further tumor progression cannot be controlled, the treatment plan will need to be changed or even the eye removed.
Vaccination is usually not allowed for 6 months after chemotherapy.

References

1、The Retinoblastoma Diagnosis and Treatment Guidelines
2、The Chinese Expert Consensus on the Diagnosis and Treatment of Retinoblastoma in the Unilateral Intraocular Stage (2019)
3、Ophthalmology (9th Edition), People's Health Publishing House
4、National Cancer Institute (NCI) Retinoblastoma Treatment (Professional Edition): https://www.cancer.gov/types/retinoblastoma/patient/retinoblastoma-treatment-pdq#_43
5、National Cancer Institute ( National Cancer Institute (NCI) Treatment of Retinoblastoma (Patient Edition): https://www.cancer.gov/types/retinoblastoma/patient/retinoblastoma-treatment-pdq#_43
6. https://www.cancer.net/ cancer-types/retinoblastoma-childhood/introduction
7. Ma JM, Wang XN. Issues that need attention in the diagnosis and treatment of retinoblastoma. Chinese Journal of Pediatric Hematology and Oncology.2015;20(3):118-120
8, Ophthalmology (3rd edition), Peking University Medical Press.

References:

Audit specialists

Ma Jianmin, Chief Physician, Department of Ocular Oncology, Peking Tongren Hospital, Capital Medical University, Beijing, China

Personal introduction:
https://baike.baidu.com/item/%E9%A9%AC%E5%BB%BA%E6%B0%91/1491068#viewPageContent