Retinoblastoma

Introduction to retinoblastoma Retinoblastoma (RB) is the most common intraocular malignant tumor in infants and young children. It is the most serious and most harmful malignant tumor in infants and young children. There are serious threats and harms to vision and life. Occurred in the retinal nucleus, has a family genetic predisposition, mostly occurs under 5 years old, can be single or both eyes or at the same time, the disease is prone to intracranial and distant metastasis, often endangering the lives of children, so early detection, early diagnosis Early treatment is the key to improving cure rate and reducing mortality. basic knowledge The proportion of illness: 0.0035% Susceptible people: no special people Mode of infection: non-infectious Complications: vitreous opacity retinal detachment glaucoma

Cause of retinoblastoma

(1) Causes of the disease

Genetic factors (40%)

About 40% of the cases are of hereditary type, which is caused by the genetics of the parents of the disease or gene carriers, or by the mutation of the normal parents' germ cells, which is autosomal dominant. Such patients have an early onset, and about 85% of them are affected by both eyes. There are multiple lesions, and the second malignant tumor is prone to occur. About 15% of the cases are monocular, which may be due to dysplasia of the retinoblastoma gene. It is generally accepted that the external manifestation rate of this disease is about 90%. Clinically, bilateral retinoblastoma, a family history of monocular retinoblastoma or a multifocal monocular retinoblastoma are classified as hereditary.

Chromosomal aberrations (25%)

A few genetic cases (about 5%) have somatic chromosome aberrations. The main manifestation is the presence of the long arm of the chromosome 13 in the peripheral blood lymphocytes. Different cases have different lengths of missing segments, but all involve the long arm 1 region 4 band (13q14) of chromosome 13, and the smallest missing segment is 13q14.2 by high-resolution chromosome banding. In addition to retinoblastoma, these patients have different chromosomal deletion segments, often accompanied by systemic abnormalities of varying severity. Mainly manifested as mental retardation and developmental delay, there may also be microcephaly, multi-finger malformation and congenital heart disease.

Virus infection (10%)

The virus is caused by parasitic growth in the human body and can cause the disease caused by the virus. Mainly manifested as fever, headache, general malaise and other symptoms of systemic poisoning and local symptoms caused by viral hosts and invading ocular tissues and organs leading to inflammatory damage.

Cell mutation (20%)

The cerebral cells of the patients with the disease are caused by mutations in the retinoblasts. They are not hereditary, and the onset is late. Most of them are monocular, single lesions, and the second malignant tumor is not easy to occur.

(two) pathogenesis

1.Rb gene mutation

The Rb gene is the first tumor suppressor gene discovered by humans. The discovery of the Rb gene is recognized as an important milestone in human oncology research, cell cycle research. The Rb gene is located at 13q14, with a total length of about 180kb and a total of 27 exons. It is transcribed into a long 4.7 kb mRNA encoding Rb protein with 928 amino acid residues. About 80% of retinoblastomas can be found in Rb gene mutations. There are four main types: non-function (null) mutation, reading In frame mutation, promoter mutation (point mutation and methylation) and LOH, the Rb gene in the reading frame still has some normal functions. The detection of early Rb gene mutation mainly depends on Southern hybridization. PCR and direct DNA sequencing can accurately predict whether the retinoblastoma will be inherited by comparing the Rb gene mutation status of the patient's tumor and peripheral blood leukocytes. The Rb gene mutation has also been found to be widely present in many other malignant tumors.

2.Rb protein and Rb pathway

Rb protein is currently considered to be the main regulator of cell growth, development, and canceration in all tissues of the human body. It inhibits cell growth, canceration, and promotes development and differentiation. Rb protein is localized in the nucleus and has a molecular weight of approximately 110 kDa. Rb can be expressed in all tissues of human body. Protein, but the expression characteristics are different at different developmental stages. In most retinoblastomas and many other malignant tumors, the expression of Rb protein is deleted or decreased. Rb protein has multiple domains, the most important is A/B binding pocket. (pocket), Rb protein can bind to various proteins through A/B binding bag, such as viral oncoprotein (SV40 large T antigen, adenovirus E1A protein, papilloma E7 protein), E2F protein, Rb protein and E7 Inactivation of protein binding may be the pathogenesis of papillary virus carcinogenesis (such as human cervical cancer). Rb protein inhibits the transcriptional activity of a variety of genes involved in cell cycle progression by binding to E2F protein, thereby inhibiting cell cycle progression.

Human cells also have two proteins P107 and P130 with similar structure and function to Rb protein, which together constitute the Rb protein family. The protein binding function of Rb protein is affected by its phosphorylation state, only non-phosphorylated or hypophosphorylated. Rb protein can bind to other proteins, and its phosphorylation state is determined by cyclin and cell cycle-related protein kinase (CDK); CDK activity is controlled by kinase kinase inhibitor (CKI). The main CKIs are P16, P19, P21, P27, P57, etc.; the activity of CKI is controlled by various intracellular or extracellular signals (such as trauma, ischemia, etc.), such that cell signals, CKI, CDK and cells Cyclin, Rb protein family, E2F protein, and cell cycle-associated genes together constitute a regulatory pathway that transmits cellular signals to cell cycle-associated genes step by step, the Rb pathway. It has been confirmed that all tumors in humans have abnormalities in the Rb pathway.

3. Multi-staged retinoblastoma

(1) Initiation phase: The Rb gene is inactivated by two mutations, and the whole malignant transformation process is initiated. First, benign retinoblastoma is formed. Without further mutation, the tumor cells can stop dividing due to further differentiation, and the tumor is still. 1 mutation 10% is inherited by parents, and most of them are newly formed at different stages of embryonic development. Many factors in this period can lead to mutation of Rb gene, such as European report in vitro fertilization (IVF) The incidence of retinoblastoma in infants is significantly increased, which may be related to the mutagenic effect of Rb gene by ovulation granules used in large quantities in IVF.

(2) Stage of malignant transformation: After the third mutation (M3) benign retinoblastoma becomes retinoblastoma, M3 is likely to be related to chromosomal abnormalities such as i(6p) present in retinoblastoma, which can prevent cells Apoptosis and cell differentiation occur, and individuals with Rb mutations are 2000 times more likely to develop retinoblastoma than other tumors, while Rb mutations are widely present in other tumors, and the retina is so sensitive to Rb mutations, most likely Related to M3.

(3) Progression stage: retinoblastoma accumulates more mutations such as 1q+, 16q-, etc., and the lesions are further deteriorated.

Retinoblastoma prevention

It is recommended that the immediate family members of the child have at least one eye examination, and other children in the family should be examined for retinoblastoma; adults need to undergo retinoblastoma examination, which is a non-malignant tumor caused by the same gene. The immediate family members of cancer can analyze their DNA to see if they have a gene for retinoblastoma.

There are currently no effective preventive measures for retinoblastoma, but regular follow-up observation of treated patients and families at high risk is a positive preventive measure. Another positive measure that can be taken now is genetic counseling and production. Pre-diagnosis to reduce the birth of the child.

Follow-up

For each patient with retinoblastoma, after treatment, a follow-up observation plan should be developed based on its clinical, pathological findings and Rb gene mutation characteristics (genetic or non-genetic), for each of the high-risk families born. Infants should also have regular fundus examination under general anesthesia. If conditions permit, consider <1 year old, once every 3 months; <2 years old, once every 4 months; 3 to 5 years old, once every 6 months 6 to 7 years old, once every 4 years, 15 times.

2. Genetic counseling

How to predict the risk of the offspring of a patient's offspring or their parents is an important issue in reducing the birth and guiding follow-up of children with retinoblastoma. Genetic counseling is an important measure to achieve this goal. Currently, the retina can be performed at two levels. Genetic counseling for blastoma.

(1) Family-based genetic counseling: calculated according to the penetrance rate of 80% to 90% of retinoblastoma.

(2) Genetic counseling by detecting mutations in the Rb gene: DNA samples can be taken from peripheral blood leukocytes and retinoblastoma tissues, and various gene mutation detection techniques such as Southern hybridization, SSCP, DGGE, etc., gene dose detection technology For example, quantitative PCR and direct DNA sequencing can be applied. Due to cost and time limitation, it is impossible to detect all the 180 kb sequences of Rb gene in the clinic. It is generally concentrated in the vicinity of 27 exons and exons 0-20 bp. Intron sequences (about 4 kb in total), the Rb gene mutation type can be the whole gene deletion, or small to point mutation, generally two mutations can be found in the tumor tissue (can be the same or different), if in the peripheral blood One of the mutations in leukocytes can be judged as hereditary retinoblastoma. If there is no mutation in peripheral blood leukocytes, it can be judged as non-genetic retinoblastoma, relative to patients with hereditary retinoblastoma. Blood can be taken to check whether there is a mutation in the same Rb gene. If there is such a mutation, there is a 90% risk of illness in the child and the child. If not, the risk is low. At the time of genetic counseling, attention should be paid to mosaic and low penetrance.

3. Prenatal diagnosis

Rb gene mutation detection has been successfully applied to clinical prenatal diagnosis. For the fetus of the hereditary retinoblastoma family, amniocytes can be detected for Rb gene mutation at 28 to 30 weeks of gestation. If there is a mutation in the family Rb gene, it is best. Termination of pregnancy; if the parents of the fetus are unwilling to terminate the pregnancy, they can undergo a transvaginal B-ultrasound examination at 33 to 35 weeks of gestation, 1 or 2 times a week to observe whether a tumor is formed in the fetal eye. If the tumor has formed, the labor can be induced at 35 weeks of gestation. Immediately, the tumor was treated with laser. There were reports of retinoblastoma with 35 weeks of induction and laser treatment of the above pregnancy, which not only retained the eyeball, but also retained good vision.

Retinoblastoma complications Complications vitreous opacity retinal detachment glaucoma

Systemic metastasis will occur: metastasis along the blood and lymph to the whole body. According to statistics, the brain and meninges occupy the first place, the cranial muscles are second, the lymph nodes and long bones are again, the abdominal organs are most common in the liver, and the tumor development is different. There are many different complications during the period, including vitreous opacity, retinal detachment, and neovascular glaucoma.

Symptoms of retinoblastoma Common symptoms Visual impairment Black and white pupils appear yellow-white reflective retinal detachment Large corneal pseudo anterior chamber empyema surface of the iris is formed... High intraocular pressure sclera grape swollen strabismus

According to the performance and development process of the tumor, it can be divided into four stages.

1. Intraocular growth period:

When the eye begins to grow in the eye, the external eye is normal. Because the child is young, he or she cannot tell whether there is any visual impairment. Therefore, the early stage of the disease is generally not easy to be discovered by the parents. When the tumor proliferates into the vitreous or close to the crystal, the pupil area will have a yellow light reflection, so it is called the black Mongolian cat's eye. At this time, the pupil is often enlarged due to visual impairment and dilated pupils, white sputum or strabismus.

Fundus changes: visible round or oval, clear boundary, single or multiple, white or yellow nodular bulge, uneven surface, different sizes, new blood vessels or bleeding points. Tumors originate from the inner nuclear layer, and are called endogenous to the vitreous body. White lumps of turbidity can be seen in the vitreous. Those originating from the outer nuclear layer are prone to choroidal growth and often retina. A solid flat detachment without cracking occurs. Slit lamp examination, there may be tumor cell colonies in the anterior chamber, the formation of pseudo anterior chamber empyema, post-corneal deposition, the formation of gray-white tumor nodules on the surface of the iris, can provide some clinical basis for early diagnosis.

2. Glaucoma period:

As the tumor gradually grows in volume, the content of the eye increases, causing an increase in intraocular pressure, causing secondary glaucoma, eye pain, headache, nausea, vomiting, and redness. Children's eye wall wall elasticity is large, long-term high intraocular pressure can make the ball wall dilate, the eyeball expands, forming a special so-called "bull eye" appearance, large cornea, corneoscleral swelling, etc., so it should be differentiated from congenital glaucoma.

3. Extraocular period:

(1) The earliest occurrence is that the tumor cells spread along the optic nerve to the skull. The optic nerve is thickened due to the erosion of the tumor tissue. If the optic nerve pores are destroyed, the optic nerve pores are enlarged, but even if the optic nerve pores are normal on the X-ray film, The possibility of post-balloon and intracranial transfer cannot be excluded.

(2) The tumor penetrates the sclera into the sac, causing the eyeball to protrude; it can also cause corneal staphyloma or piercing the cornea to grow outside the ball, and even protrude beyond the cleft palate to grow into a huge tumor.

4, systemic transfer period:

Metastasis can occur in any phase, such as a tumor that occurs near the optic nerve head, even if it is small, there may be optic nerve metastasis before the glaucoma, but generally the metastasis is most pronounced in this period. Transfer route:

(1) Most of the optic nerve or cleft palate into the skull.

(2) Transfusion to the bone and liver or other organs of the body.

(3) Part of the lymph node that is transferred to the vicinity via lymphatic vessels.

Examination of retinoblastoma

Laboratory inspection

1. Urine check:

The amount of vanillmandelic acid and homovanicillic acid in the urine increased, positive for diagnosis, but negative for Rb.

2. When the blood-aqueous barrier is intact, the concentration of lactate dehydrogenase (LDH) in the aqueous humor is higher than the serum value. When the ratio of the two is greater than 1.5, it suggests the possibility of Rb, the activity of lactate dehydrogenase (LDH). Determination: When the LDH value in aqueous humor is higher than the serum median value, the ratio of the two is greater than 1.5, which strongly suggests that retinoblastoma may be.

3. Determination of aqueous humor:

In patients with retinoblastoma, the aqueous humor and plasma lactate dehydrogenase (LDH) increased, and the aqueous humor and plasma phosphoisomerase (PGI) also increased, but in the late stage of Coats disease, when the retinal damage was wider, aqueous humor and plasma Lactate dehydrogenase and phosphoisomerase are also increased.

4. Cytological examination:

The extraction of aqueous humor or vitreous for cytological examination may be helpful for the diagnosis and differential diagnosis of this disease, but it may promote the spread of tumor through the puncture hole of the eye wall to the outside of the ball. Therefore, it should not be easily used. The cerebrospinal fluid is extracted from the lumbar puncture for cytology. Examination and bone marrow smear examination have great reference value for judging tumor metastasis.

5. Genetics examination: understanding the chromosomal condition.

6. Histopathological examination:

(1) Light microscopy: more tumor necrosis is seen under the tumor. The calcification is often seen in the necrotic area. The basophilic substance is often seen on the blood vessel wall. It is generally considered to be the DNA released by the dead tumor cells. Cellular changes can divide retinoblastoma into undifferentiated and differentiated types: 1 undifferentiated: irregularly arranged tumor cells; cell morphology varies widely, can be round, oval, polygonal or irregular The cytoplasm is small, the nucleus is large and deeply stained, the division is more common, and the degree of malignancy is higher. Due to the rapid growth of the tumor, the blood supply is insufficient, and the tumor tissue away from the blood vessel can be largely necrotic, and the survival tumor cells surrounding the periphery of the blood vessel can be Coral-like or finger-like arrangement, called pseudo-daisy-shaped arrangement, 2 differentiation type: mainly marked with chrysanthemum-like structure, and first, Flexner-Wintersteiner chrysanthemum: tumor cells are square or low columnar, forming around a central cavity Chrysanthemum-shaped, the nucleus is located at the end away from the central cavity, relatively small, more cytoplasm, less mitotic figures, lower degree of malignancy, this type of chrysanthemum is unique to retinoblastoma, It is Homer-Wright chrysanthemum: the cells are arranged radially around a group of nerve fibers. This type of chrysanthemum is still found in neuroblastoma and neuroblastoma, and the third is fleurettes: the photoreceptor-like components are petal-like protrusions. In the central cavity, seen in better differentiated cases, the degree of malignancy is lower.

(2) Ultrastructure: Undifferentiated retinoblastoma cells are closely arranged, without interstitial tissue, occasionally showing intermediate connections, large cell morphology, large nuclear, pleomorphic, multinuclear and multinuclear phenomena. The cytoplasm is small and rich in free ribosomes. The tumor cells with photoreceptor differentiation components are arranged in a ring shape. The center is an acid mucopolysaccharide cavity containing anti-phosphozyme. The adjacent cells are connected by an intermediate connection. The tumor cells are columnar and nucleus. Smaller, located at the end away from the central cavity, each cell has only one nucleus, one nucleolus in the nucleus, more cytoplasm, the main organelles are mitochondria, microtubules, rough endoplasmic reticulum and Golgi, some cell tips There are cilia extending into the central cavity, the cross-section is 9+0 type, and some of the cilia have a spherical expanded structure with a small number of parallel-arranged membrane structures. The above structure has similar characteristics to normal retinal photoreceptor cells. It can be considered that retinoblastoma is derived from retinal embryonic cells.

(3) Immunohistochemistry: Whether retinoblastoma originates from neurons or glial cells is a long-standing debate. It has not been determined so far. Immunohistochemical staining shows that most tumor cells have neuronal differentiation characteristics (such as NSE staining positive), also has the characteristics of glial cell differentiation (such as GFAP staining positive), in the transgenic retinoblastoma mouse model, the tumors are from the inner granular layer, often characterized by amacrine cells, more reasonable The explanation is that retinoblastoma may originate from a more primitive retinal cell, the retinoblast, that differentiates into neurons and glial cells.

Film degree exam

1. Eyelid X-ray photos:

Retinoblastoma can show abnormal calcification on the orbital X photograph.

2. Ultrasound exploration:

When the child is seen because of strabismus or "cat's eye", the tumor is generally larger, and the ultrasound has a typical performance, which is of great significance for diagnosis. The tumor often has calcification, which is characterized by high reflection with sound and shadow, and a few tumors have grown. Fast, liquefaction, necrosis without calcification, low reflection, eyeball can be normal or increased, measuring the axial axis can identify short white eyelids (primary vitreous tissue hyperplasia), tumor can be single or multi-focal, diffuse Less, the surface contour is irregular, no calcification, because the child does not cooperate during the examination, often use sedatives, should be double-eye examination, if necessary, repeat the examination.

3. Electronic computed tomography (CT scan) and magnetic resonance (MRI scan):

CT and MRI scans can not only find and describe the location, shape and size of the tumor, but also detect the enlargement of the optic nerve caused by the spread of the tumor to the outside of the eye, the mass in the sac and the intracranial metastasis. CT scan can also show the tumor. Calcification is of great value for diagnosis. (1) High-density mass in the eye: (2) Calcified plaque in the mass, 30 to 90% of cases have this finding as a basis for diagnosis; (3) Increased optic nerve and enlarged optic nerve hole, Explain that the tumor spreads into the brain.

4. Fundus image acquisition:

Regular photography and imaging of fundus tumors is helpful for diagnosis and judgment of the disease, which can guide the treatment well. Currently widely used is a fundus wide-angle camera RETCAM, which can be used in surgery.

5. Gross eye typing:

Generally, yellow-white tumors in the retina can be seen under the naked eye. Dense calcifications are often seen. According to the naked eye, there are three types of retinoblastoma: 1 endogenous: the tumor originates from the inner layer of the retina and grows into the vitreous. Early detection for fundus examination; 2 Exogenous type: The tumor originates from the outer nuclear layer of the retina, grows along the subretinal space and the choroid direction, causing retinal detachment. It is difficult to find tumor mass in the early stage of ophthalmoscopy. 3 Infiltration type: Tumor dispersion Sexual infiltration of the whole layer of the retina, no obvious mass, accounting for 1.5% of all retinoblastoma, more common in non-genetic retinoblastoma.

Fluorescein fundus angiography: early in the arterial phase, the tumor is fluorescing, the venous phase is enhanced, and it can penetrate into the tumor tissue. Because of the late fluorescence, it is valuable in diagnosis.

Others: still can be used for isotope scanning, scleral transillumination, carcinoembryonic antigen and so on.

Rb develops to three, four stages is generally easy to diagnose, but it is more difficult in the first and second stages. During this period, white reflective or yellow-white tissue blocks can be seen in the posterior pupil of the lens called leukoria. .

Diagnosis and diagnosis of retinoblastoma

diagnosis

According to medical history, age and clinical symptoms.

Differential diagnosis

Typical cases can be diagnosed by medical history and clinical examination, but atypical cases, especially when the retina is occluded to cover the tumor or due to hemorrhage, and the inflammatory reaction causes vitreous opacity, the diagnosis is difficult, often misdiagnosed as other eye diseases, other eye diseases can also be Misdiagnosed as retinoblastoma, clinically there are many eye diseases with yellow-white reflection in the pupil should be identified with this disease.

1. Metastatic endophthalmitis and uveitis:

After high fever and acute infectious diseases in children, pathogens (bacteria, viruses, etc.) cause retinal vascular occlusion, forming a localized yellow-white lesion, which leads to vitreous abscess, which is yellow-white pupil, in addition to pediatric granulomatous uveitis, peripheral uveal Inflammation is sometimes white, history, ultrasound, radiography and anterior chamber cytology can be identified.

2. Coats disease:

Most occur in male children and adolescents over 6 years old, with a longer course of disease, slower development, extensive abnormal expansion of retinal vessels, often accompanied by hemangioma, large white exudation under the retina, often accompanied by hemorrhage and cholesterol crystallization, and then secondary retina It is white and has a white pupil. Ultrasound examination has no substantial mass echo. The fundamental nature of Coats disease is the retinal outer hemorrhage combined with exudative changes. Although there is localized proliferation, even a bulge or retinal detachment is formed. The course of the disease is slow, the lesions are extensive, and the gray-white exudates are distributed behind the retinal blood vessels. In addition to the exudates, hemorrhage spots and bright spots (cholesterol crystals) are also observed, and the blood vessels, especially the veins, show dilatation, torsion, distortion, and There are microangiomas, the lesions are often progressive, new and old exudates can alternate, bleeding can enter the vitreous, can form proliferative vitreoretinopathy, the patient is older than 6 years old, and is a young male, monocular Involved, ultrasound examination, often no substantial changes.

3. Retinopathy of prematurity (posterior lens fibrosis, Terry syndrome):

Most occur in premature infants who have been treated with high concentrations of oxygen. Oxygen causes primary vasoconstriction and secondary vascular proliferation in the immature retina, ie, the incompletely vascularized retina, often occurring in both eyes 2 to 6 weeks after birth. Retinal arterioles become thinner, varicose veins dilate, new blood vessels form, after which all blood vessels dilate, retinal edema, turbidity, uplift, hemorrhage, proliferative vascular cords in the bulge, growth in the vitreous, late vitreous vascular hyperplasia, connective tissue Forming, pulling the retina to form wrinkles, after the lens is visible, the machined membrane can be seen. After the dilated sputum, the ciliary process elongated by the mechanical membrane can be seen. The medical history and ultrasound examination can be used for identification.

4. Primary vitreous hyperplasia:

This disease is a congenital abnormality of the eye. The reason is that the vitreous artery in the fetal period has not disappeared and is proliferated. It is characterized by thick grayish white connective tissue and new blood vessels behind the lens. Generally, white pupils are found after birth. More than 90% of infants are monocular, with small eyeballs, shallow anterior chamber, and pupillary abnormalities. Ultrasound can help identify.

5. Retinal hypoplasia, congenital retinal folds, congenital choroidal defects and congenital retinal myelinated nerve fibers are congenital fundus abnormalities, severe cases can be white pupils, fundus examination can be identified.

6. Young nematode granuloma:

When the eggs of toxocara canis are ingested by children, the larvae hatched in the intestine invade the eye through the ciliary artery or the central retinal artery. It can be seen that the retina forms an isolated white granuloma, and the child may be accompanied by white blood cells. And the increase of eosinophils, liver, and the increase in serum antibody titer of Canine axil.

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