Introduction to retinoblastoma

Introduction

It is the most serious and most harmful malignant tumor in infants and young children.Retinoblastoma(retinoblastoma, RB) is the most common intraocular malignancy in infants and young children, with serious threats and harm to vision and life. Occurred in the nuclear layer of the retina, with a family genetic predisposition, mostly occurring under the age of 5, 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.

Cause

(1) Causes of the disease

The exact cause is unknown. 6% are autosomal dominant and 94% are sporadic cases. 25% of them are genetic mutations, and the rest are somatic mutations. Some people think that it is related to viral infection factors. Genetic type and location of Rb gene: 90% of retinoblastoma (including monocular and binocular cases) showed sporadic morbidity, and 10% of cases were familial. Retinoblastoma can be divided into two major categories: genetic and non-genetic. There are three cases:

1 About 40% of the cases are of hereditary type, which is caused by the parents of the disease or gene carriers, or by the mutation of 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.

2 About 60% of the cases are non-genetic, and the cerebral cells of the patients are caused by mutations in the retinoblasts. They are not hereditary, and the onset is late. Most of them are monocular, single lesions, and second malignant tumors are not easy to occur.

3 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.

(two) pathogenesis

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

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

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 the Rb protein is affected by its phosphorylation state, and only the non-phosphorylated or hypophosphorylated Rb protein can bind to other proteins. Its phosphorylation state is determined by cyclin and cell cycle-related protein kinase (CDK); CDK activity is controlled by cyclin dependent kinase inhibitor (CKI). The main CKIs are P16 and P19. , P21, P27, P57, etc.; CKI activity is controlled by various intracellular or extracellular signals (such as trauma, ischemia, etc.). Thus, the cellular signal, CKI, CDK and cyclin, Rb protein family, E2F protein, and cell cycle-related genes together constitute a regulatory pathway that transmits cell signals to cell cycle-related genes step by step, namely the Rb pathway. It has been confirmed that all tumors in humans have abnormalities in the Rb pathway.

3. Multi-staged retinoblastoma

(1) Start-up phase: The Rb gene is inactivated by two mutations, and the entire malignant process is initiated, first forming a benign retinoblastoma. Without further mutation, the tumor cells can stop dividing due to further differentiation, and the tumor is still. The first mutation 10% is inherited by parents, and most of them are newly formed at different stages of the embryonic development process. A variety of factors during this period can lead to mutations in the Rb gene, such as the significant increase in the incidence of retinoblastoma in infants with in vitro fertilization (IVF) in Europe, possibly in combination with the ovulation-promoting agent used in IVF for the Rb gene. It is related to change.

(2) Stage of malignant transformation: After the third mutation (M3), benign retinoblastoma becomes retinoblastoma. M3 is likely to be associated with chromosomal abnormalities such as i(6p) present in retinoblastoma, which can prevent apoptosis and cell differentiation. In addition, individuals with mutations in the Rb gene are 2000 times more likely to develop retinoblastoma than other tumors, and Rb mutations are widely present in other tumors. The retina is so sensitive to mutations in the Rb gene that it is likely to be associated with M3.

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

symptom

Undifferentiated type: The tumor cells surround a column of blood vessels, in which part of the tumor cells are necrotic and calcinous. This is called pseudosette. This type has a low degree of differentiation and a high degree of malignancy, but is sensitive to radiation.

Differentiation type: also known as neuroepithelial type, consisting of square or low columnar tumor cells, the cells are arranged around the central cavity in a circular shape, called a rosette. This type has a higher degree of differentiation, lower malignancy, but is not sensitive to radiation.

In some cases, the degree of differentiation of tumor cells is higher, and there are structures similar to photoreceptors, with the lowest degree of malignancy. Tumor cells cluster like a fleurette, also known as photoreceptor differentiation. Recently, this type is called retinocytoma, which is different from general retinoblastoma.

1. According to the general development process of retinoblastoma, the clinical can be divided into four phases, namely the intraocular growth phase and the intraocular pressure increase phase (glaucomaPeriod), extraocular expansion period and systemic metastasis period. Due to different tumor growth sites, growth rates and differentiation levels, clinical manifestations are not consistent. For example, a tumor that grows near the optic disc or around the retina can cause early invasion of the optic nerve or ciliary body to the extraocular eye. It does not go through the glaucoma and directly enters the extraocular expansion phase; as in the case of clinical diagnosis of glaucoma, pathology Checks may have an eye expansion.

(1) Intraocular growth phase: Its early symptoms and signs are visual impairment and fundus changes. Early lesions can occur anywhere in the fundus, but more often below the pole. If the tumor occurs in the inner layer of the retina, it tends to grow into the vitreous, called endogenous. Fundus examination revealed a tumor with a round or elliptical shape, unclear borders, white or yellow-white nodules, and neovascularization or hemorrhage on the surface. Nodules vary in size, 1/2 to 4 disc diameters or larger. It can happen alone or several nodules at the same time. Due to the fragility of the tumor tissue, the tumor mass can spread in the vitreous and anterior chamber, causing vitreous opacity, pseudo anterior chamber empyema, post-corneal deposition or formation of gray-white tumor nodules on the surface of the iris. If the tumor occurs in the outer nuclear layer of the retina, it tends to grow to the choroid, called the exogenous type, often causing retinal detachment, and the detached retinal vascular angulation.

The change in vision is related to the location of the tumor. If the tumor is small, located around the fundus, it does not affect the central vision; if the tumor is located in the posterior pole, the volume is small, it can still cause vision loss earlier, and can produce strabismus or nystagmus; if the tumor is full of intraocular or retinal When you detach, your vision is lost.

Due to loss of vision, the pupil is enlarged, and yellow-white reflection is seen through the pupil, which is called "black-haired cat eye". At present, according to domestic and foreign literature reports, the clinical still uses "cat eyes" as the most common early symptoms of the disease. In fact, when the pupil appears yellow-white reflective, the condition has developed to a considerable extent. Therefore, clinically, infants and young children can be regarded as clues for early detection of the disease, and the fundus should be fully examined to diagnose or rule out the disease.

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.

(2) Increased intraocular pressure: Increased intraocular tumor growth, especially when affecting the choroid and anterior chamber, can lead to elevated intraocular pressure, causing obvious headache, eye pain, conjunctival hyperemia, corneal edema and other glaucoma symptoms. An enlarged tumor can also cause ischemia of the posterior eye, causing neovascularization of the iris, thereby forming neovascular glaucoma. Due to the large elasticity of the eye wall of children, under the action of high intraocular pressure, the eyeball expands and the cornea becomes larger, forming "bull eye" or scleral staphyloma, large cornea, corneal scleral staphyloma, etc., so it should be differentiated from congenital glaucoma.

(3) extraocular expansion period: the way the tumor spreads to the outside of the eye is as follows: through the cornea or sclera to form a mass protruding from the cleft palate, the surface often has hemorrhagic necrosis; through the sclera or along the sclera (such as the vortex vein , ciliary blood vessels, etc.) spread to the sacrum to form a mass, which makes the eyeball protrude; spread along the scleral sieve plate, the optic nerve or the central blood vessel of the retina to the inside or inside the skull. The latter is the most common way to expand. 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. However, even if the optic nerve pores are normal on the X-ray film, the ball cannot be excluded. The possibility of post and intracranial transfer. 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 metastasis: advanced tumor cells can be transferred to the brain via the optic nerve; lymphatic vessels to lymph nodes, soft tissue metastasis; or blood circulation to bone, liver, spleen, kidney and other tissues and organs. Eventually lead to death.

2. In addition to the above typical clinical manifestations and afterwards, some cases have the following special performances:

(1) Spontaneous regression and retinocytoma of retinoblastoma: A small number of retinoblastomas can be spontaneously regressed without treatment, mainly manifested as eyeball atrophy. May be due to enlarged tumors caused by central retinal vascular occlusion, causing tumor and whole eye ischemia, tumor necrosis, eyeball atrophy collapse, manifested as clinical "self-healing"; may also be related to tumor apoptosis, because studies have shown that Rb Gene inactivation can cause both abnormal proliferation of retinal cells and a large number of apoptosis of retinal cells. Approximately 50% of spontaneously regressed retinoblastoma can recur.

The spontaneous regression of retinoblastoma should be distinguished from "retinocytoma". Retinal cell tumors have long been recognized as a major form of spontaneous regression of retinoblastoma before being recognized in 1982, but are currently considered to be an independent disease, a benign tumor of the retina caused by inactivation of the Rb gene. There is no evidence that retinoblastoma can "spontaneously resolve" to retinoblastoma without treatment. Retinal cell tumors are characterized by non-progressive gray-white translucent masses of the retina, often accompanied by calcification, pigmentation disorders, and chorioretinal atrophy. Retinoblastoma accounts for 1.8% of all retinoblastomas. Like retinoblastoma, retinoblastoma can be monocular or binocular, and can be single or multifocal. Often found after the age of 6, the average age of diagnosis is 15 years. Such patients may have a family history of retinoblastoma, and may have retinoblastoma in the other eye or in the same eye. Retinal cell tumors have a good prognosis, but 4% of them may become retinoblastoma, which is characterized by tumor enlargement and vitreous dissemination. There are two possible mechanisms for the development of retinoblastoma: one is that the Rb gene mutation occurs in the relatively differentiated but not mature retinoblasts; the other is that the Rb gene mutation is "relatively benign" and the mutant Rb protein is still partially normal. Function is a manifestation of low penetrance retinoblastoma.

(2) Trilateral retinoblastoma (TRB): Some patients with retinoblastoma may be associated with intracranial tumors such as pineal tumors and primary neuroblasts on the sella or adjacent to the sella tumor. These intracranial tumors are histologically similar to retinoblastoma, but not to intracranial metastases of retinoblastoma. Because of the multiple appearance of ocular retinoblastoma patients, and the pineal and retinal photoreceptor cells have phylogenetic and individual relationship, such intracranial tumors are called "trilateral retinoblastoma." The incidence of TRB in patients with binocular retinoblastoma is 5% to 15%. The incidence in all patients with retinoblastoma is about 3%. Chemotherapy can significantly reduce the incidence of TRB. Neuroimaging screening can detect TRB in advance, and intracranial tumors with a maximum diameter of <15 mm have a good prognosis. From 1971 to 2003, 120 cases of TRB were reported worldwide, 40% had a family history, 88% were binocular retinoblastoma, and 12% were monocular retinoblastoma. 83% of intracranial tumors are located in the pineal gland and 17% are located on the sella. The average age at diagnosis of ocular tumors was 5 months, and the average age at diagnosis of intracranial tumors was 26 months. The average survival time of the intracranial tumor was 9 months. If an independent intracranial midline tumor is found in a child with retinoblastoma, whether it is with either bilateral retinoblastoma or successfully treated bilateral retinoblastoma for a while When it appears, the possibility of TRB should be considered. Clinical should be differentiated from intracranial metastasis of retinoblastoma.

(3) Second malignant neoplasm (SMN) in retinoblastoma survivors: The cure rate and survival rate of retinoblastoma are also greatly improved due to the improvement of diagnostic and therapeutic levels. Follow-up observation of long-term survivors revealed that some patients developed other malignant tumors several years later, which was called a second malignant tumor. There are at least 23 histological types, such as osteosarcoma, fibrosarcoma, reticular sarcoma, malignant melanoma, neuroblastoma, nephroblastoma, acute lymphocytic leukemia, Hodgkin's disease, sebaceous gland cancer, epidermis Carcinoma, thyroid cancer, etc. The most common of these is osteosarcoma. In the case of femoral osteosarcoma, the prevalence of retinoblastoma survivors is 500 times that of the general population. It was originally thought that the occurrence of the second malignant tumor was caused by radiotherapy of retinoblastoma, but the analysis of the large-scale case found that many patients occurred away from the radiological site, such as the femur; and some patients who had not undergone radiotherapy also developed the second malignancy. Tumors, indicating that some of the second malignant tumors have nothing to do with radiation. On the other hand, most of the second malignant tumors (88.2% to 97.5%) occur in patients with hereditary retinoblastoma (binocular patients, or monocular patients with a family history), and some patients may also have third and fourth Even the fifth malignant tumor. Therefore, the occurrence of the second malignant tumor is considered to be mainly related to heredity. Using molecular biology techniques, it was found that retinoblastoma gene (Rb gene) is deleted or expressed in the second malignant tumor tissue of patients with retinoblastoma (such as osteosarcoma, fibrosarcoma, malignant reticuloma). Abnormalities strongly confirm that the occurrence of a second malignant tumor is associated with a change in the Rb gene. It is generally believed that the occurrence of a second malignant tumor is associated with a change in the Rb gene, but early (less than 12 months of age) extraradiation therapy in patients with hereditary retinoblastoma can significantly increase the incidence of a second malignancy. Once a second malignant tumor occurs, the prognosis is poor.

diagnosis

According to the clinical manifestations combined with the results of the auxiliary examination, it is easy to determine the diagnosis.

Identification

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 the vitreous opacity caused by bleeding and inflammation, the diagnosis is difficult, often misdiagnosed as other eye diseases. Other eye diseases can also be misdiagnosed as retinoblastoma. Clinically, many eye diseases with yellow-white reflection in the pupil should be distinguished from the disease.

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

2. Coats disease occurs mostly in male children and adolescents over 6 years old, with a longer course and slower development. Retinal blood vessels are widely abnormally dilated, often accompanied by hemangioma, and large white exudation under the retina, often accompanied by hemorrhage and cholesterol crystallization, and then secondary retinal detachment with white pupils, no substantial mass echoes by ultrasonography. The fundamental nature of Coats disease is the retinal outer hemorrhage combined with exudative changes. Although there is a localized proliferation, even a bulge or a retinal detachment is formed. However, the course of the disease is slow, the lesions are extensive, and the gray-white exudates are distributed behind the retinal vessels. In addition to exudate, bleeding spots and bright spots (cholesterol crystals) are also observed. Blood vessels, especially veins, show dilatation, torsion, distortion, and microangioma. The lesions are often progressive, and new and old exudates may alternate. If the bleeding enters the vitreous, proliferative vitreoretinopathy may form. The patient is older than 6 years old, and is a young man with monocular involvement. Ultrasound examinations often have no substantial changes.

3. Retinopathy of prematurity (posterior lens fibrosis, Terry syndrome) occurs mostly in premature infants who have been treated with high concentrations of oxygen. Oxygen causes primary vasoconstriction and secondary to immature retina, the incompletely vascularized retina. The proliferation of blood vessels. Often 2 to 6 weeks after birth, the incidence of both eyes. Early retinal arterioles become thinner, varicose veins dilate, and new blood vessels form. After that, all blood vessels dilated, retinal edema, turbidity, uplift, hemorrhage, and hyperplastic vascular cords in the bulge, which grew into the vitreous. In the late vitreous, vascular hyperplasia, connective tissue formation, traction of the retina to form wrinkles, and after the lens is visible, the mechanized membrane can be seen. After the dilated sputum, the ciliary process elongated by the mechanical membrane can be seen. Medical history and ultrasound examinations are available for identification.

4. The original vitreous hyperplasia is the 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 behind the lens with new blood vessels. Generally, white pupils are found after birth, and more than 90% of infants born in full-term are monocular. Mostly accompanied by small eyeballs, shallow anterior chamber, pupil abnormalities. Ultrasound can help identify.

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

6. Young worm granuloma Toxocara canis eggs are ingested by children. The larvae hatched in the intestines invade the eye through the ciliary artery or central retinal artery. The retina forms an isolated white granuloma. The child may be accompanied by an increase in white blood cells and eosinophils, a large liver, and an increase in the serum antibody titer of Canine axil.

complication

Systemic metastases occur: metastasis along the blood and lymph. According to the statistics of the affected organs, the brain and meninges occupy the first place, followed by the cranial muscles, and again the lymph nodes and long bones. The abdominal organs are most common in the liver. Different stages of tumor development can produce a variety of different complications. Including vitreous opacity, retinal detachment, neovascular glaucoma and the like.

treatment

Western medicine treatment

Treatment: (a) treatment

Retinoblastoma as a hereditary intraocular malignant tumor in children affects the life, vision, facial shape and psychological development of the child. Diagnosing involves ophthalmology, pediatrics, and obstetrics. The treatment involves ophthalmology, oncology (radiation, chemotherapy), pediatrics, and anesthesiology. Therefore, in the treatment of retinoblastoma, we must emphasize multidisciplinary, multi-center cooperation. The goal of retinoblastoma is to save lives first, followed by keeping the eye and part of the eyesight. The principle of treatment should be based on the tumor and systemic involvement of the tumor. The choice of method should be based on the size and extent of the tumor, unilateral or bilateral, and the general condition of the patient.

Commonly used treatments include surgical treatment (including eyeball removal, eyelid removal), external radiation therapy, topical therapy (photocoagulation therapy, cryotherapy, heat therapy, superficial scleral patch radiotherapy) and chemotherapy. In the past 10 years, the concept of treatment of retinoblastoma has undergone major changes in the world, mainly in the combination of chemotherapy and multiple aggressive local therapy (SALT) to first-line treatment, while external radiation therapy Reduced to second-line treatment, eyeball removal for third-line treatment. This change is thought to be a new era in the treatment of retinoblastoma. Generally, for intraocular retinoblastoma (RE1 to 4) with good general condition and limited lesions, local or chemotherapy combined with local treatment can be selected for monocular or binocular; for intraocular phase with large lesions Retinoblastoma (RE4 to 5), or the tumor has spread to the eye, you can choose surgery, if necessary combined with external radiation therapy and chemotherapy. External radiation therapy should be avoided for hereditary retinoblastoma.

1. Chemotherapy Simple chemotherapy alone does not completely cure retinoblastoma, but it can often significantly reduce tumor volume (known as chemoreduction), secondary retinal detachment, and reduction of metastasis. So that local treatment can be implemented. For hereditary retinoblastoma, chemotherapy can also prevent the emergence of new tumor foci and second malignant tumors (especially intracranial trilateral retinoblastoma). It has been used in combination with topical therapy to treat intraocular retinoblastoma. Commonly used drugs areVincristine,EtoposideCarboplatin,Cyclophosphamide, cyclosporin A and the like. The commonly used regimen is the VEC regimen, ie, vincristine, etoposide, and carboplatin are combined for 6 courses of treatment, each course of treatment is 2 days, and the course of treatment is 3 weeks apart. Because retinoblastoma is highly susceptible to drug resistance, large doses of cyclosporin A can sometimes be reversed for short-term use. Examination of anesthesia (EUA) under general anesthesia was performed 1 to 3 days before the start of each course of treatment, and changes in the condition were recorded. At the same time, cryotherapy of the retina was feasible to increase the accumulation of chemical drugs in the eye. Generally, after 2 to 3 courses of treatment, the tumor is significantly reduced. At this time, local treatment (such as photocoagulation therapy and cryotherapy) is started at the same time as EUA. After 6 courses of treatment, EUA should be performed once every 3 to 6 weeks to record changes in the condition or local treatment. After the condition is stable, the interval of EUA is gradually extended. This treatment regimen allows approximately 80% of RE1 to 3, 30% of RE4 to 5 retinoblastoma patients to be exempt from external radiotherapy and enucleation, but for tumors that are disseminated in the vitreous cavity and subretinal space. The cell effect is poor.

For ocular retinal and systemic metastatic retinoblastoma, chemotherapy is often combined with surgical treatment (including eyeball removal, eyelid removal) and external radiotherapy. For cases with choroidal, scleral, and sieve plate metastasis, chemotherapy can prevent further tumor metastasis to the body. For retinoblastoma at systemic metastases, high-dose chemotherapy with autologous stem cell rescue (ASCR) can be performed: first, routine dose chemotherapy is performed to reduce possible tumor cells in the bone marrow and blood. The hematopoietic stem cells are then cryopreserved from the bone marrow or blood; a large dose of chemotherapy is then performed, and the frozen autologous stem cells are finally returned to restore the suppressed hematopoietic system. Chemotherapy of retinoblastoma often produces systemic side effects, and should be performed in conjunction with pediatric and oncologists in clinical applications.

2. Topical treatment Local treatment is becoming more and more important in the treatment of retinoblastoma. The effect is closely related to the thickness of the tumor. It is generally considered that <2mm is a small tumor, only simple local treatment; 2 ~ 4mm is a moderately large tumor, can be treated with local treatment, but combined with chemotherapy is safer; > 4mm for large tumors, local treatment must be combined with chemotherapy. There are four methods for commonly used topical treatments:

(1) Photocoagulation treatment: Photocoagulation treatment focuses the light from a strong light source on the retinal tumor area through the optical system, and cuts off the blood vessels entering the tumor by condensation of light (about 75 ° C), or directly condenses the surface of the tumor tissue to promote Tumor cells are necrotic and atrophic. It is mainly suitable for small small tumors that do not invade the optic disc, the fovea of the macula, the choroid and the vitreous. Commonly used are 532nm indirect laser, 1064nm continuous wavelength Nd:YAG indirect laser, 810nm indirect laser, 810nm diode transscleral direct laser. The method is to blaze the tumor for 2 times around the tumor, and the energy should reach the blood vessels that make the nearby retina white and supply the tumor, but can not destroy the Bruch membrane, so as to prevent the tumor cells from spreading to the choroid and generating choroidal neovascularization in the future. The tumor surface can be photocoagulated at the same time, but a large spot is applied to prevent the tumor cells from diffusing into the vitreous cavity. Larger tumors can be photocoagulated multiple times, and after a few weeks of treatment, the tumor can resolve into a flat scar.

(2) Cryotherapy: Cryotherapy 24 hours before the start of chemotherapy can significantly increase the concentration of intrachemotherapy drugs. Cryotherapy is suitable for smaller tumors, especially for peripheral tumors in the equator that are more difficult to treat with radiation and photocoagulation. The freezing temperature should be -110 ~ -90 ° C, each freezing point is continuously frozen for 1 min each time, thawed for 1 min, and the cycle is repeated 3 times. Tumors include ice hockey formed by freezing, and sharp ice crystals can destroy tumor structures when thawed. Effective treatment usually results in tumor regression after 2 to 3 weeks, choroidal atrophy, and the formation of flat, pigmented scar tissue. It should be noted that cryotherapy is prone to complicated retinal detachment.

(3) Heat treatment: the local temperature of the tumor is increased to about 45 °C by laser, which can increase the killing effect of carboplatin on retinoblastoma. Commonly used diode infrared laser connected with surgical microscope or indirect ophthalmoscope, the spot diameter is 0.4~2.0mm, energy is 150~1500mW, lasting 10~20min. About 80% of intraocular retinoblastoma can be controlled.

(4) Shallow scleral patch radiotherapy: suitable for cases with tumors >10 mm in diameter that have failed other local treatments. At present, 60CO and 125I patching plates are mainly used, and they are sewn on the scleral surface corresponding to the tumor, and placed for 7 days, and then released after 3.0 to 4.0 Gy.

3. External radiation therapy retinoblastoma (especially undifferentiated) is sensitive to radiation therapy, so radiation therapy is an effective treatment for the disease. However, external radiotherapy can significantly increase the incidence of second malignant tumors, and often cause facial deformities, dry eye, radiation cataracts, radiation retinopathy, etc., currently only used for extensive vitreous or subretinal dissemination. (RE5), or other treatment failures. Commonly used are 60CO treatment machines and electron accelerators, which are irradiated through the anterior or temporal side of the eye, with a total dose of 35 to 40 Gy.

4. Surgical treatment

(1) Eyeball removal: The tumor is full of eyeballs, has a risk of metastasis to the optic nerve and choroid, and has no hope of retaining useful vision (RE4~5), or combined with neovascular glaucoma as the first choice for enucleation. Surgical operation should be very gentle, in order to prevent tumor cells from entering the blood circulation, the optic nerve should be removed as long as possible, not less than 10mm. Active eye can be implanted after the eyeball is removed.

(2) Eyelid removal: If the tumor spreads to the sclera or optic nerve, it is feasible to remove the orbital content, and postoperative radiotherapy and chemotherapy should be combined.

5. Photodynamic therapy.

6, immunotherapy.

The above content is for reference only, please consult the relevant physician or relevant medical institution if necessary.

prevention

It is recommended that the immediate family members of the child have at least one eye exam. Other children in the family should be examined for retinoblastoma; adults need to undergo retinoblastoma, a non-malignant tumor caused by the same gene. For immediate relatives who have no evidence of cancer, their DNA can be analyzed to see if they have a gene for retinoblastoma.

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

1. Follow-up For each patient with retinoblastoma, after treatment, a follow-up observation plan should be developed based on clinical and pathological findings and Rb gene mutation characteristics (genetic or non-genetic). Every baby born to a high-risk family should also be given regular fundus examination under general anesthesia. If there are conditions, you can 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 every 4 years 15 times.

2. How genetic counseling predicts the risk of a patient's offspring or their parents' re-children 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. Genetic counseling for retinoblastoma can now be performed at two levels.

(1) Family-based genetic counseling: Calculated according to the penetrance rate of 80% to 90% of retinoblastoma, the genetic counseling for the risk of the disease can be referred to Table 1.

(2) Genetic counseling by detecting mutations in the Rb gene: DNA samples can be obtained from peripheral blood leukocytes and retinoblastoma tissue. A variety of gene mutation detection techniques such as Southern hybridization, SSCP, DGGE, etc., gene dose detection techniques such as quantitative PCR, direct DNA sequencing can be applied. Due to cost and time constraints, it is clinically impossible to perform a complete detection of the full-length 180 kb sequence of the Rb gene, and is generally concentrated on the intron sequence of 0 to 20 bp in the vicinity of 27 exons and exons (about 4 kb in total). The type of mutation in the Rb gene can be either a deletion of the entire gene or a small to point mutation. Generally, two mutations (which may be the same or different) can be found in the tumor tissue. If one of the mutations is also present in the peripheral blood leukocytes, it can be judged as hereditary retinoblastoma if there is no mutation in the peripheral blood leukocytes. It can be judged as non-genetic retinoblastoma. Relatives of patients with hereditary retinoblastoma can be blood-stained to check whether there is the same mutation in the Rb gene. If there is such a mutation, there is a risk of 90% of the illness of the child and the child. If not, the risk is low. At the time of genetic counseling with DNA testing, 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 taken for mutation of Rb gene at 28 to 30 weeks of gestation. If there is a mutation in the family Rb gene, it is best to terminate the pregnancy; if the fetus is unwilling to terminate the pregnancy, 33 to 35 weeks of gestation, vaginal B-ultrasound examination, 1 or 2 times a week, to observe whether the formation of tumors in the fetal eye, if the tumor has formed, can induce labor in the 35th week of pregnancy, immediately laser treatment of the tumor. It has been reported that retinoblastoma, which was induced by labor and laser treatment for 35 weeks of the above pregnancy, not only retains the eyeball, but also retains good vision.