Brain Tumors

Brain Tumors Essential Information

Summarize

        A brain tumor is a tumor that occurs in the brain and consists of an abnormal proliferation of cells in the brain, usually originating in brain tissue or structures in and around the brain (e.g., meninges, cranial nerves, pituitary gland, pineal gland, etc.).

        The brain is an important part of the human central nervous system (the central nervous system includes the brain and spinal cord). The human brain consists of three main parts:

        ● The brain is located at the top of the head in the skull and is the largest part of the brain. Our thinking, learning, problem solving, emotions, speech, reading, writing and voluntary movement are all controlled by the brain.

        ● The cerebellum is located in the lower back of the brain, almost in the middle of the back of our skull, and it controls movement, balance, and posture.

        ● The brainstem is the part of the central nervous system that connects the brain to the spinal cord and is located in the lowermost part of the brain, almost at the back of our neck. The brainstem controls breathing, heart rate, and the nerves and muscles used for seeing, hearing, walking, talking, and eating.

        The brain and spinal cord together form the central nervous system. Brain tumors are the main category of CNS tumors. In children, 98-99% of CNS tumors are brain tumors.

        Brain tumors include benign and malignant brain tumors. Among them, malignant brain tumors in children are the second most prevalent childhood cancer and the malignant solid tumor with the highest incidence in children, accounting for nearly one-third of all childhood cancers.

        Benign brain tumors grow and compress nearby brain areas, but rarely spread to other tissues. Malignant brain tumors, on the other hand, grow rapidly and some types of tumors can spread. When a tumor presses on an area of the brain, it may affect the normal functioning of that brain area. Therefore, both benign and malignant brain tumors require treatment. Children's brain tumors are not treated in the same way as adult brain tumors and have many of their own characteristics, so the same treatment ideas used for adult brain tumors cannot be applied to the diagnosis and treatment of children's brain tumors.

 

Epidemiological

incidence of a disease

        According to the Brain Tumor Registry of the United States (CBTRUS), the incidence of malignant central nervous system tumors among children under 14 years of age in the United States between 2012 and 2016 was 5.74 per 100,000, which has surpassed the incidence of childhood leukemia as the most prevalent childhood cancer in the United States at that time, as well as the most lethal childhood cancer. Nearly 5,000 children and adolescents 19 years of age and younger are diagnosed with CNS tumors each year in the U.S., with an Asian incidence rate of 3.37 cases per 100,000 people. The most common types of childhood brain tumors in children under 19 years of age in the United States are, in descending order: hairy cell astrocytomas, pineal region tumors, non-specific (i.e., molecularly indeterminate) malignant gliomas, and embryonal tumors (64.9% of which are medulloblastomas).

        The incidence rates in other parts of the world were relatively slightly lower, with the incidence rate in Japan estimated at 3.61 cases per 100,000 children per year, in Italy at 3.46 cases per 100,000 children per year, in Germany at 2.6 cases per 100,000 children per year, in Australia at 3 cases per 100,000 children per year, and in Taiwan Province of China at 1.7 cases per 100,000 children per year.

        According to the statistics of patients with central nervous system tumors at Beijing Tiantan Hospital between 2001 and 2005, the five most common types of brain tumors in Chinese children aged 17 years and younger were, in order, astrocytoma, craniopharyngioma, medulloblastoma, germ cell tumors, and ventricular tubular meningioma.

 

Etiolog & Risk factors

risk factor

        For most childhood brain tumors, the exact etiology is unclear. Ionizing radiation, genetic factors and some inherited syndromes may increase the risk of brain tumors.

1) Basic etiology

        The main cause of primary brain tumors in children is the mutation of cells in the skull that proliferate uncontrollably and become tumor cells. However, for most childhood brain tumors, the exact cause is not known.

2) Predisposing factors

i) Ionizing radiation

        Ionizing radiation is a type of electromagnetic radiation, mainly referring to nuclear radiation (e.g., the atomic bomb explosion in Japan, the Chernobyl nuclear accident in the former Soviet Union, etc.). X-rays and gamma rays used in medicine also belong to this category. Radiation from everyday electrical appliances (e.g., cell phones, microwave ovens) does not fall into the category of ionizing radiation.

        Exposure of the skull to ionizing radiation increases the risk of brain tumours in children, leading in particular to an increased risk of meningiomas, gliomas and nerve sheath tumours. In patients with acute lymphoblastic leukemia, high doses of cranial irradiation increase the risk of gliomas sixfold and meningiomas tenfold.

ii) Genetic factors

        Many patients with childhood brain tumors carry disease-associated genetic mutations. Also, a number of inherited disorders caused by mutations in specific genes increase the risk of brain tumor development. Such inherited disorders include:

● Neurofibromatosis (NF)

        Neurofibromatosis is an autosomal dominant neurocutaneous disorder in which patients develop multiple tumors in various locations throughout the body and often have a higher chance of developing other tumors. Neurofibromatosis includes neurofibromatosis type 1, neurofibromatosis type 2, and nerve sheath tumors, with neurofibromatosis type 1 being the most common.

:: Tuberous sclerosis

        Tuberous sclerosis is an autosomal dominant neurological skin disease that causes benign tumors to grow throughout the body, including a variety of benign tumors of the brain, kidneys, and skin.

:: Von Hippel-Lindau syndrome (VHL syndrome)

        VHL syndrome is an autosomal dominant disorder associated with hemangioblastoma, pancreatic cysts, neuroendocrine tumors, renal tumors, and pheochromocytoma. It may increase the risk of intracranial hemangioblastoma development.

●Basal cell nevus syndrome

        Basal cell nevus syndrome, also known as Gorlin syndrome, or nevus-like basal cell carcinoma syndrome, is caused by inherited mutations in the tumor suppressor gene patch (PTCH) gene. It is associated with an increased risk of medulloblastoma.

●Li-Fraumeni syndrome (L-Fraumeni syndrome)

        Li-Fameni syndrome is an autosomal dominant disorder that increases the incidence of a variety of malignant tumors, such as soft tissue sarcoma, osteosarcoma, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma.

● Glioma polyposis syndrome (Turcot syndrome)

        Glioma polyposis syndrome is an inherited disorder of unknown etiology with multiple colon polyps as the main symptom. Individuals with glioma polyposis syndrome have a higher risk of developing brain tumors (mainly medulloblastoma and glioma) and colon cancer.

 

Classification & Stage

        Brain tumors in children are graded and classified primarily based on the Central Nervous System Tumor Grading and Classification System.

1. Disease classification

        The World Health Organization (WHO) grades CNS tumors based on their histological characteristics. This histological grading is a means of predicting tumor progression and is a key clinical factor influencing treatment choices, particularly the use of adjuvant radiotherapy and specific chemotherapy regimens. Typically, grades I and II are referred to as low-grade and grades III and IV as high-grade.

        It is important to note that although tumor grading is an important basis for treatment option selection, not all brain tumor treatments are planned according to tumor grading.

●WHO Grade I: Tumors with low proliferative potential that may be cured by surgical resection only.

● WHO Grade II: Tumors are usually infiltrative and have low proliferative activity, but tend to recur easily. Some grade II tumors tend to progress to tumors with a higher degree of malignancy. For example, low-grade diffuse astrocytomas may transform into mesenchymal astrocytomas or glioblastomas, and similar transformations may occur in oligodendrogliomas and oligodendroglial astrocytomas.

● WHO Grade III: Usually used for lesions with histologic evidence of malignancy, including nuclear heterogeneity and active mitotic activity. In most cases, patients with grade III tumors require adjuvant radiotherapy and/or chemotherapy.

● WHO Grade IV: Cytologically malignant, mitotically active, necrosis-prone tumors usually associated with rapid disease evolution and lethal outcome both preoperatively and postoperatively, e.g., glioblastomas, most embryonal tumors, and many sarcomas. For CNS tumors, extensive peripheral tissue infiltration and a propensity for craniospinal dissemination characterize some grade IV tumors.

Type of disease

1) Classification according to histologic and molecular features

Currently, brain tumors in children are classified according to the 2007 and 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System. Among them, the 2007 WHO classification is mainly based on histologic features, and in 2016, molecular features were added as the basis for staging. Common pediatric brain tumors are classified as follows:

● Glioma

Gliomas originate from glial cells (e.g., astrocytes, oligodendrocytes, and ventricular meningeal cells), and according to the Brain Tumor Registry of the United States (CBTRUS), nearly half of all central nervous system tumors in children and adolescents are gliomas. Depending on the cellular origin, gliomas can be further classified as astrocytomas, ventricular meningiomas, and oligodendrogliomas.

○Astrocytoma

Astrocytomas can occur in different brain regions within the skull. Depending on their specific type, they may be graded for different WHO classifications.

Of these, low-grade astrocytomas are the most common brain tumors in children and adolescents, with a predominance of hairy cell type astrocytomas, in addition to diffuse astrocytomas.

High-grade astrocytomas include mesenchymal astrocytoma, H3K27M mutant diffuse midline glioma, and glioblastoma.

○Oligodendroglioma

Oligodendrogliomas originate from oligodendrocytes and can be divided into low-grade oligodendrogliomas (WHO grade II) and high-grade mesenchymal oligodendrogliomas (WHO grade III).

○Ventricular meningioma

Ventricular meningiomas originate in the cells of the ventricular membrane and can occur in the brain and spinal cord. In children, nearly 90% of all ventricular meningiomas are intracranial ventricular meningiomas that occur in the brain, accounting for 10% of brain tumors in children and adolescents. Most children's ventricular meningiomas occur in the subdeltoid region, in or around the fourth ventricle.

● Embryonal tumors

Embryonal tumors are all high-grade and highly malignant. Common embryonal tumors in children's brain tumors include medulloblastoma, atypical teratoid/rhabdomyosarcoma (AT/RT), non-specific CNS embryonal tumors, embryonal tumors with multilayered chrysomelic clusters, medulloepitheliomas, CNS neuroblastomas, and CNS embryonal tumors with rhabdomyosarcomatous features. Of these, medulloblastoma is the most common, accounting for 64.9% of embryonal tumors in children and adolescents.

○Medulloblastoma

Medulloblastoma, which occurs mainly in the posterior cranial fossa and cerebellum, is the most common malignant brain tumor in children, accounting for 6-7% of all pediatric central nervous system tumors.

● Saddle region tumors

Saddle region tumors are primarily located in the upper region of the pterygoid saddle and originate from the Rucker's capsule in the saddle region. These tumors account for approximately 15% of all childhood CNS tumors and include primarily pituitary tumors and craniopharyngiomas.

● Neuronal and mixed neuronal gliomas

Neuronal and mixed neuronal gliomas have a proportion of cells that differentiate into neurons. Of these tumors, all are low-grade, except for mesenchymal ganglion cell gliomas, which are WHO grade III.

Neuronal and mixed neuronal gliomas can be classified into 13 different types, including ganglion cell gliomas, infantile pro-fibroplastic astrocytomas/ganglion cell gliomas, embryonic dysplastic neuroepithelial tumors, and papillary glial neuronal tumors.

:: Germ cell tumors

Germ cell tumors originate from primitive germ cells. Germ cell tumors that occur intracranially account for 3-4% of all central nervous system tumors in children. Germ cell tumors can be divided into germ cell tumors and non-germ cell tumors of the germ cells. The latter include embryonal carcinomas, yolk sac tumors (also called endodermal sinus tumors), choriocarcinomas, and teratomas. Of these, teratomas are further divided into mature teratomas and immature teratomas. Among them, mature teratomas are benign tumors, while the rest are malignant tumors.

About 2/3 of intracranial germ cell tumors occur in the pineal and paraspinal regions and 1/3 in other midline regions of the brain.

● Meningioma

Tumors that occur in the meninges and originate from a special type of cell in the meninges called a cap cell. Meningiomas account for 2-3% of all childhood CNS tumors and vary in malignancy and may be WHO grade I-III.

:: Central nervous system leukemias and lymphomas

Less than 1% of CNS tumors in children are CNS leukemias and lymphomas, i.e., leukemia or lymphoma cells invade the CNS.

2) Classification according to the site of origin

Depending on the site of origin of brain tumors in children, they are classified as supratentorial, paraspinal, and infratentorial tumors:

● Epithelial tumors, including:

  ○ Low-grade cerebral hemispheric astrocytoma: mainly WHO grade I hairy cell type astrocytoma and WHO grade II diffuse astrocytoma.

  ○ High-grade or malignant astrocytomas: mainly mesenchymal astrocytomas and glioblastomas.

  ○ Oligodendrogliomas: including low-grade malignant, mesenchymal, and mixed oligodendroglial astrocytomas.

  ○ Neuronal and mixed neuronal gliomas: there are 13 different types, mainly including ganglion cell gliomas, infantile fibroproliferative astrocytomas/ganglion cell gliomas, embryonic dysplastic neuroepithelial tumors, and papillary glial neuronal tumors.

  ○Other low-grade gliomas: mainly subventricular giant cell astrocytoma and pleomorphic yellow astrocytoma.

  ○Embryonal tumors: mainly atypical teratoid/rhabdomyosarcoma, embryonal tumors with multilayered daisy-like clusters (C19MC variant or non-specific), medullary epitheliomas, CNS neuroblastomas, CNS embryonal tumors with rhabdomyosarcoma features, and other CNS embryonal tumors.

  ○Ventricular meningioma: typical ventricular meningioma, RELA fusion gene-positive ventricular meningioma, and mesenchymal ventricular meningioma were predominant.

  ○Meningiomas: including WHO grade I, II and III meningiomas.

  ○Choroid plexus tumors: including choroid plexus papilloma, choroid plexus carcinoma, and atypical choroid plexus papilloma.

  ○ Pineal region tumors (pinealocytoma, pineoblastoma, moderately differentiated pineal parenchymal tumors, and pineal region papillary tumors)

  ○Germ cell tumors

  ○ Brain metastases from malignant tumors outside the nervous system: quite rare.

● Parasaddle tumors, including:

  ○Craniopharyngioma

  ○ Mesencephalic astrocytomas: astrocytomas involving the optic cross, hypothalamus, and/or thalamus, usually low-grade astrocytomas, including astrocytomas, with a predominance of WHO grade I, hairy cell-type astrocytomas, and WHO grade II, diffuse astrocytomas.

  ○Germ cell tumors: both germ cell tumors and non-germ cell tumor germ cell tumors may occur.

  ○Embryonic tumors: rare in the paraspinal region.

  ○ Glioma: rare in the paraspinal region.

● Subtentorial (posterior cranial fossa) tumors, including:

  ○Cerebellar astrocytoma: the most common is hairy cell astrocytoma, followed by diffuse astrocytoma, mesenchymal astrocytoma and glioblastoma also occur but are less common.

  ○Medulloblastoma

  ○Ventricular meningiomas: mainly typical ventricular meningiomas and mesenchymal ventricular meningiomas.

  ○Brainstem gliomas: diffuse midline gliomas are the most common, including H3K27M mutant diffuse midline gliomas and other diffuse midline gliomas. This is followed by hairy cell type astrocytomas, with focal extended cervical myeloma, parietal extended cervical myeloma, and extranodal extended cervical myeloma being the most common.

●Atypical teratoma/rhabdomyosarcoma

● Choroid plexus tumors: choroid plexus papillomas and choroid plexus carcinomas predominate.

 

 

 

Clinical manifestations

        Symptoms of brain tumors in children may be non-specific (i.e., not unique to children with brain tumors) and may vary depending on the age of the child and the location of the tumor, and there may be a long interval between the onset of symptoms. Brain tumors may invade the surrounding brain tissue, compressing adjacent brain areas, and may also cause increased intracranial pressure, resulting in a range of signs and symptoms. Increased intracranial pressure can be caused either directly by the tumor pressing on the relevant tissues or by hydrocephalus due to obstruction of the flow of cerebrospinal fluid.

        In addition, brain tumors in children may be misdiagnosed because their symptoms may be nonspecific, such as developmental delays. In this regard, it is important to understand the normal developmental characteristics of the child's age group.

        When the tumor occurs episodically, symptoms are usually nonspecific, with headaches being the most common. Seizures or localized neurological deficits can also be more common.

        If the tumor is located in the posterior cranial fossa, common symptoms are headache, nausea and vomiting, ataxia (loss of balance), gait abnormalities, and optic papilla edema.

        If the tumor invades the brainstem, common symptoms are gait and coordination abnormalities, and cranial nerve palsies.

        In infants, because the cranial sutures are not fused, the child is able to adapt to the elevated intracranial pressure without acute neurologic damage but with macrosomia. Nausea and vomiting are also routine. In addition, infants may not be able to express certain symptoms (e.g., headaches) and therefore may simply appear irritable.

        In addition, in some rare cases, newborns are born with congenital brain tumors. Congenital brain tumors are rare and account for less than 2% of all childhood brain tumors. Newborns usually present with macrosomia, some will be born with a tense fontanelle, and others may develop hydrocephalus due to the tumor itself or the effect of the tumor on the ventricular system.

        Children with congenital brain tumors rarely show neurological symptoms at first. In some cases, prenatal ultrasound can detect lesions before delivery. Fetal magnetic resonance imaging (MRI) can help in the prenatal diagnosis of such lesions.

        Among the more common features of prenatally diagnosed cases of congenital brain tumors is excessive amniotic fluid in pregnant women. This is due to a dysfunction of the fetal hypothalamus, which results in impaired swallowing and an inability to swallow amniotic fluid, leaving the pregnant woman with excess amniotic fluid. Due to the risk of tumor rupture and massive blood loss in the fetus, the pregnant woman may need to undergo a cesarean section to prevent a difficult delivery.

        In the 2010 Guidelines for the Diagnosis of Brain Tumors in Children, prepared by the Department of Pediatric Oncology at Birmingham Children's Hospital in the United Kingdom, it is recommended that a child be taken for imaging of brain tumors if the following symptoms are present:

        ● Persistent (more than 4 weeks) headache that meets any of the following:

            ○Waking up in pain when I sleep

            ○Headache when I'm awake

            ○Children under 4 years old

            ○With disorientation or confusion.

        ● Persistent morning sickness

        ● Visual problems, including optic papilla edema, optic nerve atrophy, new onset of nystagmus, decreased visual acuity (not due to refractive problems), and field of view reduction.

1. Headache

         Headache is the most common manifestation of brain tumors, and about one-third of affected children will experience this symptom. Headaches caused by brain tumors may be localized or full-blown. If the child is an infant or young child, he or she may not be able to articulate the source of his or her discomfort and is more likely to present as easily irritated.

        Headaches due to brain tumors are usually thought to be the result of elevated intracranial pressure and often come on early in the morning and are relieved by vomiting.

2. Nausea and vomiting

        Nausea and vomiting are common symptoms of childhood brain tumors and occur in children of all ages. Tumors located in the posterior cranial fossa are particularly likely to cause nausea and vomiting.

3. Ataxia and gait abnormalities

        Childhood brain tumors located in the posterior cranial fossa often cause ataxia and coordination difficulties. Initial symptoms may be more subtle, manifesting as clumsiness of movement, deterioration of writing, changes in speech, or difficulty with motor skills, such as the inability to run or jump properly.

4. Cranial nerve palsy

        Cranial nerve palsy is usually caused by a brainstem tumor and may cause diplopia, nystagmus, inability to turn the eyes inward when looking sideways, facial paralysis, salivation, and difficulty swallowing. Young children may not be able to articulate what diplopia feels like, but they may cover one eye with their hand or tilt their head to the side.

        Tumors in the pineal region or midbrain may cause Parrino syndrome (also known as superior colliculus syndrome, midbrain parietal syndrome, and superior elevation paralysis syndrome). Parrino syndrome causes a range of eye symptoms, such as loss of pupillary light response, loss of control of eye movements, ptosis, and blurred vision.

5. Visual impairment

        Impaired vision may result from a variety of causes, such as cranial nerve palsies (e.g., diplopia) caused by brainstem tumors, optic papillary edema due to elevated intracranial pressure, or lesions of the optic nerve.

Tumors at the site of the optic crossings often cause complex visual field defects and impaired vision. In contrast, tumors located behind the optic tract may cause some degree of hemianopsia.

6. Epilepsy

        Epilepsy is one of the symptoms of brain tumors in children, especially low-grade supratentorial brain tumors. Seizures may occur alone or may be accompanied by other brain tumor signs or symptoms.

7. Optic papilla edema

        Optic papilla edema is bilateral optic nerve papilla edema caused by intracranial pressure. The optic nerve papilla is the place in the retina where nerve fibers converge to travel out of the eye. When intracranial pressure affects the optic nerve sheath, it triggers optic papilloedema. About 10-15% of children with brain tumors have this sign, and it is more common in children with posterior cranial fossa lesions.

8. Large head deformity

        In infants, since the cranial sutures have not yet fused, the child can adapt to the expansion of the intracranial mass and the increase in intracranial pressure without seriously impairing the neurologic status, but can manifest a large head deformity as a result. For this reason, macrosomia is the most common symptom of brain tumors in infancy. Children in infancy may also present with enlarged fontanels and/or open cranial sutures.

        Macrosomia can also occur in older children with brain tumors, but is less common than in children in infancy.

9. Developmental delays and behavioral changes

        Infants and young children may exhibit developmental delays. In older pediatric patients, increased intracranial pressure may lead to changes in behavior or personality, and even decreased academic performance.

10. Endocrine abnormalities

        In children with optic cross tumors, pituitary tumors, or hypothalamic tumors (e.g., craniopharyngiomas), endocrine abnormalities such as growth disturbances, urolithiasis, precocious puberty, or obesity may occur. A few children with hypothalamic tumors may develop mesencephalic syndrome manifesting as severe wasting but normal linear growth, increased appetite and hyperactivity.

 

Clinical Department

        The diagnosis of brain tumors in children is made primarily through neuroimaging, such as magnetic resonance imaging (MRI) or CT, to identify the lesion. Confirmation of the specific tumor type is done through histology.

Relevant Section

        Pediatric neurosurgery, or neurosurgery

 

Examination & Diagnosis

1. Relevant examinations

1) Physical examination

        Physical examination means checking the general signs of the body, including checking for signs of disease, such as lumps or any other unusual manifestations, and also asking about the patient's health habits, previous illnesses and treatment history.

2) Neurological examination

        This is a series of tests that examine brain, spinal cord and nerve function, and is used to check a patient's mental state, coordination and ability to walk normally, as well as muscles, senses and reflexes.

3) Imaging

        Imaging tests such as CT and magnetic resonance imaging (MRI) are helpful in the diagnosis of all brain tumors, in understanding the extent of tumor spread, and in evaluating the efficacy of tumor treatment.

i)CT

        CT is usually the first imaging study performed because it is more widely available, requires a shorter examination time, and usually does not require sedation. CT is the first choice for an initial examination in an emergency situation, such as a child suspected of having elevated intracranial pressure but who is in an unstable state. It must be noted, however, that a normal CT result does not completely rule out the possibility of a brain lesion.

        However, CT has an advantage in the demonstration of calcification, and this is especially true for subventricular ventricular meningiomas.

ii) Magnetic Resonance (MRI) and Enhanced Magnetic Resonance (Enhanced MRI)

        MRI is the best neuroimaging method for brain tumors. It provides more detailed images of substantial lesions than CT and is more sensitive in detecting tumors in the posterior cranial fossa, subarachnoid space, and soft meninges.

        An imaging technique based on magnetic resonance has also been derived from enhanced magnetic resonance, which has also been used in brain tumor imaging. In this type of imaging, a substance called gadolinium is injected into a vein into the circulatory system, and the gadolinium collects around the cancer cells, making them appear brighter in the image. Enhanced MRI can provide information suggestive of specific tumor types.

        MRI can also help stage tumors that have a tendency to spread in the soft meninges (e.g., medulloblastoma, atypical teratoid/rhabdomyosarcoma, ventricular meningioma, and high-grade astrocytoma).

iii) PET scan (electron emission tomography)

        PET scanning is not currently used by all healthcare providers as part of the standard screening for brain tumors, but it can still provide useful information to supplement the results of an MRI scan.PET scanning can differentiate between areas of malignant lesions with a high metabolic rate and areas of benign lesions with a low metabolic rate or surrounding normal tissue.

        For tissue biopsies, PET scanning can be used to identify areas within a tumor with the highest metabolic rate, guiding the neurosurgeon to sample the most malignant areas within the tumor. It can also be used to differentiate recurrent tumors from tumor changes produced during radiation therapy.

4) Lumbar puncture examination (cerebrospinal fluid cytology)

        A lumbar puncture, also known as a lumbar puncture, is a method of collecting cerebrospinal fluid from the spinal cord. A lumbar puncture places a needle in the cerebrospinal fluid between two bones in the spine and around the spinal cord and removes a sample of the fluid. A pathologist will examine the cerebrospinal fluid sample under a microscope for signs of tumor cells. The amount of protein and glucose in the sample may also be examined; higher-than-normal protein or lower-than-normal glucose may both be signs of an underlying tumor.

5) Biopsy and Pathologic Examination

        For most brain tumors, if imaging confirms the presence of a mass in the child's brain, tissue from the mass is obtained for histopathologic diagnosis. This is typically done after surgical resection. Postoperative treatment options, including radiation and/or chemotherapy, also depend on the histologic diagnosis.

2. Differential diagnosis

        Because many signs and symptoms of CNS tumors are nonspecific, they may be misdiagnosed as common childhood illnesses (e.g., viral gastroenteritis, tension headaches, and migraines). Other rare neurological disorders that present similarly to brain tumors include brain abscesses, intracranial hemorrhages, nonneoplastic hydrocephalus, arteriovenous malformations, aneurysms, or inert viral infections.

        It is important to note that children with CNS tumors often have more than one tumor-related symptom or sign, which can help physicians differentiate them clinically from other disorders. For example, headaches in children with CNS tumors are often accompanied by other manifestations such as vomiting, visual impairment, unsteady gait, changes in behavior or academic performance, sleep disturbances, and growth disturbances. To clearly differentiate CNS tumors from other diagnoses, any child suspected of having a CNS lesion should undergo imaging.

        Headaches caused by brain tumors are sometimes misdiagnosed as migraine or tension headaches and can be differentiated by other central nervous system manifestations that accompany the headache. Patients with headaches generally have one or more other symptoms associated with brain tumors, such as vomiting, visual impairment, gait instability, changes in behavior or school performance, sleep disturbances, and/or growth disturbances. If a child presents with persistent headaches, a thorough history and physical examination is needed to evaluate for any signs and symptoms associated with a brain tumor. If the child has a history of headaches with other signs of increased intracranial pressure or limited neurologic symptoms, neuroimaging should be performed for further evaluation.

 

 

Clinical Management

 

 

        The primary treatment strategy for pediatric brain tumors is through a combination of surgery, radiation therapy, and chemotherapy. After evaluation by a pediatric neurosurgeon, total surgical excision and tissue testing is performed whenever possible. Radiation therapy and chemotherapy are adjunctive treatments based on the structure of the tumor tissue test.

1. Surgical treatment

1) Surgical treatment of brain tumors in children

        Usually, open surgery is the first choice for the treatment of brain tumors in children. With surgery, tumor tissue can be obtained for histopathological diagnosis and the tumor can be removed over as large an area as possible. The goal of surgery is to achieve complete resection of the tumor. However, complete resection is often limited and difficult to achieve because of the risk of permanent neurological deficits. As a result, children may require postoperative adjuvant treatments such as radiation therapy and chemotherapy.

        For more deeply located tumors, such as diffuse endophytic gliomas located in the brainstem region and gliomas located in the optic crossings, open surgery is risky and may result in irreversible neurological sequelae. In these diseases, tissue for histopathologic diagnosis can be obtained by magnetic resonance imaging (MRI) or CT-guided stereotactic biopsy techniques. For tumors within or around the ventricles of the brain, neuroendoscopic techniques are also an option for biopsy sampling.

        In order to counteract the damage to brain tissues and critical neurological functions in the brain caused by large tumor resection, microsurgery can be used to enhance the safety of the surgery. Microsurgery allows the interface between the tumor and the surrounding normal tissue to be more clearly visible, resulting in safer surgical resection and a lower incidence of postoperative complications.

If the tumor is located in a critical functional part of the brain, or if the tumor has blurred boundaries with its surrounding tissues, the following techniques may be used to minimize damage to adjacent normal tissues:

        ● Preoperative stereotactic imaging is used to plan the surgical route to maximize tumor removal while minimizing damage to normal tissue.

        ● Intraoperative decision-making is assisted by magnetic resonance imaging (including functional MRI).

        ● Intraoperative neurophysiological monitoring of visual, auditory, and somatosensory nerve pathways involving critical functional areas to minimize damage to normal tissue.

        Timely postoperative imaging is required, preferably MRI within 24-72 hours of surgery, in order to determine the extent of tumor removal.

2) Postoperative complications

i) Hydrocephalus

        In children with brain tumors, excessive cerebrospinal fluid may accumulate after surgery and cause an increase in intracranial pressure, i.e., hydrocephalus. Therefore, after surgery to remove the tumor, the surgeon may place an external drain in the child's brain to allow excess cerebrospinal fluid, as well as tissue debris from the surgery, to drain from the skull. Other types of tubes may also be placed to allow blood that has accumulated after surgery to drain from under the scalp. The drain can usually be removed after a few days. To avoid interference with tissue debris from surgery, imaging tests such as MRI or CT scans are usually performed 1-3 days after surgery to confirm how much of the tumor has been removed.

ii) Cerebral edema

         Cerebral edema is a major problem after brain tumor surgery in children. Drugs with a corticosteroid component are usually given before and a few days after surgery to help reduce this risk.

iii) Impaired brain function

        One of the biggest problems when removing a brain tumor is the potential loss of certain brain functions after surgery. Symptoms of postoperative brain damage depend largely on the location and size of the tumor and can vary from site to site. Symptoms of impaired brain function may appear days or even weeks after surgery, so therefore the child needs to be closely monitored for physical and behavioral changes after surgery.

iv) Epilepsy

        Seizures are common in children with brain tumors, and their cause may be related to a variety of factors. Some studies have shown that children may be at higher risk for seizures in the perioperative period of brain tumor resection if they are less than 2 years of age, or if the tumor is located in the supratentorial region, or if the child has hyponatremia.

        Seizures in children with brain tumors are usually treated with anticonvulsant medications, which commonly include phenytoin, levetiracetam, valproic acid, lamotrigine, topiramate, gabapentin, and pregabalin. When choosing anticonvulsants, interactions with chemotherapeutic agents need to be considered and chosen carefully and in accordance with medical advice.

        Currently, there are no studies in children to show whether preoperative prophylactic use of anticonvulsants is effective, but relevant studies in adults have shown no role for preoperative prophylactic use. The need for postoperative prophylactic anticonvulsants should be determined in consultation with the physician in charge, depending on the child's condition.

v) Uremia

        If a child's posterior pituitary gland is damaged or removed during surgery, impaired fluid and electrolyte regulation may occur postoperatively as a result of deranged secretion of the relevant hormones, leading to urolithiasis, which needs to be treated with hormone replacement therapy.

2. Radiation therapy

1) Radiation therapy for pediatric brain tumors

        Radiation therapy (radiotherapy for short) plays an integral role in the management of pediatric brain tumors. The use of radiotherapy depends on the histological diagnosis of the tumor, the availability of effective alternatives to chemotherapy, and the age of the child. Since radiotherapy increases the risk of neurocognitive sequelae, doctors in our country usually recommend that children under the age of 3 avoid radiotherapy.

        When choosing radiation therapy, the specific volume planned to be irradiated (e.g., whether to choose localized or whole-brain, whole-spinal cord radiotherapy) and the dose of radiation therapy should take into account the location, type, and stage of the tumor, the expected pattern of spread, the availability of effective chemotherapy, and the age of the child.

        Radiotherapy for children's brain tumors is usually carried out by conventional external radiation. In addition to conventional radiotherapy techniques, three-dimensional conformal radiotherapy can accurately design the distribution of radiotherapy rays according to the structure of the tumor, which can reduce the radiation damage to normal tissues; intensity-modulated radiotherapy can adjust the distribution of radiotherapy intensity according to the structure of the tumor, which can also reduce the radiation damage to normal tissues. In addition, proton radiotherapy can also reduce the radiation to normal tissues, so it can also be used for radiotherapy of children's brain tumors.

2) Adverse Reactions

        Although radiotherapy is more damaging to tumor cells, it can still cause some damage to normal tissues, especially in infants and children whose nervous systems are still developing. Complications of cranial radiotherapy can be categorized into three stages: acute radiation reaction, early delayed radiation reaction and late radiation reaction.

        To minimize the long-term complications associated with radiation therapy, physicians often employ strategies such as lowering the dose of radiation therapy in relatively low-risk patients or using special radiation treatments such as three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, or proton radiotherapy to reduce the radiation exposure to normal tissues.

i) Acute radiation reactions

        Acute radiation reactions occur during radiotherapy treatment and result from inflammation and edema caused by brain damage, with specific symptoms including fatigue, irritability, headache, nausea, drowsiness, focal neurological deficits and fever. Sometimes corticosteroids (e.g., dexamethasone) or other medications can be used to relieve the associated symptoms. Some children may lose hair in the area of the scalp exposed to radiation.

ii) Early delayed radiation response

        Early delayed radiation reactions occur weeks to 3 months after radiotherapy and are now thought to be caused by a combination of tumor response, peritumoral edema, and neuromyelination. Symptoms of early delayed response include transient focal neurologic deficits, radiation drowsiness syndrome (characterized by extreme drowsiness and increased intracranial pressure, which in addition to drowsiness may manifest as headache, nausea, vomiting, anorexia, and irritability), or may be asymptomatic but may show enhancement on magnetic resonance imaging. At this point, it is important to note that these may be difficult to distinguish from tumor progression. Early delayed radiation reactions usually improve after a few weeks.

iii) Late radiation reactions

        Late radiation reactions occur after 90 days of radiotherapy and are usually irreversible. Late radiation reactions are the result of radiation-induced necrosis of brain tissue, diffuse cerebral white matter damage (i.e., leukoencephalopathy), secondary malignancies, and vascular disease, with common manifestations including neurocognitive impairments and social and behavioral deficits. Depending on the location of the tumor and the radiation field, other complications may occur, such as hearing impairment, hypothalamic and pituitary endocrine disorders and visual impairment secondary to cataracts, optic neuropathy, retinopathy or cortical blindness.

3. Chemotherapy

1) Chemotherapy of brain tumors in children

        The use of chemotherapy (or chemo for short) in the treatment of brain tumors depends on the type of tumor and the age of the child. Chemotherapy is commonly used in the following clinical situations:

          ● Older children with high-grade brain tumors (e.g., medulloblastoma, high-grade astrocytoma), usually in combination with surgery and radiation therapy.

          ● Infants and children with embryonal tumors, low-grade gliomas, or optic pathway gliomas. In such cases, chemotherapy is usually administered postoperatively to delay or replace radiation therapy in order to reduce or eliminate the long-term effects of radiation on infants and children.

        Because there is a natural "barrier" in the brain called the blood-brain barrier that prevents most chemotherapy drugs from entering the brain from the bloodstream, chemotherapy for brain tumors is usually given in one of the following ways:

          ● High doses or combinations of multiple chemotherapy drugs are given through an IV for chemotherapy. This method allows for higher concentrations of chemotherapy drugs in the brain.

          ● Intrathecal chemotherapy, in which chemotherapy drugs are injected directly into the central nervous system.

          ● Intratumoral chemotherapy, in which chemotherapy drugs are injected directly into the tumor tissue.

          ● Intravenous chemotherapy with infusion of hypertonic arabinose or mannitol to help chemotherapy drugs penetrate the blood-brain barrier.

2) Adverse Reactions

        Side effects of chemotherapy depend on the type of drug given, the dose, and the length of time the drug is given. General side effects can include: hair loss, mouth sores, loss of appetite, nausea and vomiting, diarrhea or constipation, increased chance of infection, easy bruising or bleeding, and fatigue. The severity of side effects is related to the type of drug, the dose and the duration of chemotherapy. Usually, these side effects go away after the treatment is over.

4. Cutting-edge treatment

        The use of targeted drugs in the treatment of malignant gliomas and other tumors has evolved as scientific research has progressed. For example, targeted drugs that disrupt the vascular endothelial growth factor (VEGF) pathway are now available to inhibit the formation of abnormal vascular systems in malignant gliomas and other tumors. These drugs include monoclonal antibodies that bind VEGF, tyrosine kinase inhibitors, and protein kinase C inhibitors.

       Other new drugs target other molecular pathways involved in tumor pathogenesis, such as epidermal growth factor, platelet-derived growth factor, integrins, the SHH pathway and histone deacetylases.

        Biological agents, such as interferon therapy and gene therapy, are also very promising new therapies in the treatment of malignant gliomas and other brain tumors.

 

Prognosis

 

1. Survival rate

        Survival rates for different types of brain tumors vary widely, depending on the age of the child and the type of tumor.

        According to the United States, the childhood brain tumor with the highest survival rate is hairy cell astrocytoma, with a five-year survival rate of 97%. And the lowest survival rates are for atypical teratoma/rhabdomyosarcoma and high-grade glioma. Of these, the five-year survival rate for glioblastoma is only 18 percent. A quarter of all children who pass away from cancer in the United States have brain tumors, especially high-grade brain tumors.

2. Sequelae

        Survivors of childhood brain tumors often have neurological, cognitive, psychological, and endocrine sequelae, which are usually due to the tumor itself, its treatment (surgery, radiation, and/or chemotherapy), or secondary tumors that occur afterwards. The risk of sequelae is elevated if the child was less than 3 years old at the time of diagnosis and treatment, or if he or she had hydrocephalus, or if he or she received whole-brain, whole-spinal cord radiotherapy.

1) Neurocognitive disorders

        Neurocognitive disorders are common complications and sequelae in children with brain tumors, usually manifested as impairment of the child's intellectual development and cognitive functioning, and learning disabilities are also one of its manifestations. According to relevant studies, the vast majority of child brain tumor survivors can complete school normally, but their grades are usually lower than other children of the same age.

2) Cerebrovascular disease

        Pediatric brain tumor patients who have received radiation therapy have an increased risk of developing advanced cerebrovascular disease (e.g., stroke) many years after treatment ends.

3) Endocrine abnormalities

        The hypothalamic-pituitary axis (HPA) is very important for human endocrinology. If the hypothalamic-pituitary axis is damaged or partially removed during surgery or damaged by cranial irradiation, endocrine abnormalities may result, which may cause thyroid disorders, urolithiasis, growth retardation, obesity, pubertal abnormalities, and infertility. In female survivors of childhood brain tumors, diagnosis before the age of 4 years and receipt of radiotherapy are associated with abnormal menarche, which may be early or delayed.

        Therefore, after the completion of oncology treatment, the child may need to receive endocrine therapy depending on the condition.

4) Secondary tumors

        Patients treated for brain tumors in childhood are at risk for developing secondary tumors decades after treatment. Based on long-term follow-up studies of survivors of childhood brain tumors, the cumulative incidence of secondary tumors is approximately 10% within 20 years of diagnosis. The most common secondary tumors include basal cell carcinomas, meningiomas, malignant CNS tumors (e.g., gliomas and astrocytomas), soft-tissue sarcomas, and thyroid cancers. The risk of developing secondary CNS tumors is related to the maximum radiation dose received to the cranial region.

        Of course, this risk should not prevent children who need radiotherapy from receiving it. However, because of this risk, close follow-up review is needed after treatment is completed. If problems arise, they can be detected and treated in a timely manner.

5) Psychological problems

        Several studies have shown that adult survivors of childhood brain tumors are more likely to be depressed compared to their siblings.

3. Rehabilitation

        If functional or speech impairment occurs as a result of the treatment of a child's brain tumor, rehabilitation in a rehabilitation unit may be considered. There is no standardized protocol for this type of rehabilitation, and it should be carried out according to the actual condition as prescribed by the doctor.

4. Complications

1) Elevated intracranial pressure

        Elevated intracranial pressure is a common complication in children with brain tumors and can be caused by tumor compression or obstructive hydrocephalus. If imaging or clinical signs show elevated intracranial pressure in a child, urgent neurosurgical intervention is needed (if hydrocephalus is present it needs to be relieved by tumor resection and/or placement of a shunt) to prevent serious injury or even life-threatening injuries.

        If the child has hydrocephalus, it will need to be relieved by tumor removal or placement of a shunt. In such cases, although tumor removal may allow the hydrocephalus to subside, preoperative cerebrospinal fluid drainage is also often required to provide temporary relief from elevated intracranial pressure and reduce the potential risk of cerebral herniation. Drainage is usually performed by placing drains outside the ventricles of the brain prior to craniotomy, and after surgery, bloody cerebrospinal fluid and debris are also drained through the drains. The drain is usually removed within a few days after the cerebrospinal fluid flow returns to normal after surgery.

        In cases of persistent obstruction in cerebrospinal fluid flow, a long-term cerebrospinal fluid shunt, such as a ventriculoperitoneal shunt, in which a catheter is placed to shunt the hydrocephalus into the peritoneal cavity, may be necessary. The feasibility of a tricuspid fundoplication may also be evaluated based on the pathologic type of the tumor, the cause of the hydrocephalus, and the current severity of the hydrocephalus.

        Patients with elevated intracranial pressure due to brain tumors are usually treated with glucocorticoids (e.g., dexamethasone) throughout the surgical period to reduce surgery-related peritumoral edema. The usual dosing regimen is preoperative intravenous or oral dexamethasone (0.25-0.5 mg/kg administered every 6 hours, with a maximum dose of 16 mg/day), which is continued intraoperatively and in the early postoperative period. In most cases, dexamethasone can be discontinued after a few days because the tumor size decreases after surgical resection. However, if the child's tumor is not amenable to resection (e.g., brainstem tumor), long-term dexamethasone therapy may be required.

2) Epilepsy

        Seizures are common in children with brain tumors, and their cause may be related to a variety of factors. Some studies have shown that children may be at higher risk for seizures in the perioperative period of brain tumor resection if they are less than 2 years of age, or if the tumor is located in the supratentorial region, or if the child has hyponatremia.

        Seizures in children with brain tumors are usually treated with anticonvulsant medications, which commonly include phenytoin sodium, levetiracetam, sodium valproate, lamotrigine, topiramate, gabapentin, and pregabalin. When choosing anticonvulsants, interactions with chemotherapeutic drugs need to be considered, chosen carefully and in accordance with medical advice.

        For example, some anticonvulsant drugs, such as phenytoin, phenobarbital, and carbamazepine, affect the expression of cytochrome P450 enzymes and need to be carefully selected for chemotherapeutic agents metabolized through this system (e.g., nitrosoureas, paclitaxel, cyclophosphamide, etoposide, topotecan, irinotecan, cetirizine, doxorubicin, methotrexate, and corticosteroids) if used concurrently to impair the efficacy of chemotherapy .

        Also, many chemotherapeutic agents alter the plasma concentrations of concomitantly administered anticonvulsants and require close attention, especially during tapering and after discontinuation.

        In addition, the anticonvulsant drug sodium valproate inhibits hepatic enzyme expression and reduces the metabolism of certain chemotherapeutic agents, leading to an increased risk of toxicity from certain chemotherapeutic agents.

        Currently, there are no studies in children to show whether preoperative prophylactic use of anticonvulsants is effective, but relevant studies in adults have shown no role for preoperative prophylactic use. The need for postoperative prophylactic anticonvulsants should be determined in consultation with the physician in charge, depending on the child's condition.

3) Impairment of the function of the nervous system

        If a large area of the brain is exposed to radiation, it may cause loss of certain brain functions, which may cause memory loss, personality changes, learning difficulties, seizures, and growth retardation. Some of these symptoms may get better with time, but others may be long-lasting. This depends on the brain area affected and the dose of radiation received.

4) Radiation necrosis

        In rare cases, large amounts of necrotic tissue form at the tumor site in the months or years following radiation therapy. Radiation necrosis can usually be controlled with corticosteroids, but in some cases surgical removal of the necrotic tissue may be necessary.

5. Recurrence and metastasis

        Recurrence of brain tumors in children varies depending on the type of pathology, but may occur many years after initial treatment. Tumor recurrence occurs because, even after treatment, a small number of tumor cells may still be present in the body. Because these cells are exceptionally small in number, they cannot be detected on examination. Over time, however, the number of these cells may increase and cause signs and symptoms or be reflected in test results.

        Recurrence of childhood brain tumors may occur at the site of the primary tumor or elsewhere in the CNS - the latter is more commonly seen in recurrence of malignant brain tumors. Metastatic recurrence outside the CNS may occur in some pediatric brain tumors, but is very rare.

        Recurrent brain tumors may have different WHO grading and molecular biological features than primary tumors. Therefore, patients may need to undergo biopsy or surgical sampling for histopathologic examination. Recurrent brain tumors are often difficult to distinguish from secondary tumors. Therefore, the specific treatment needs to be decided by the supervising physician according to the patient's condition based on the time of recurrence, tumor characteristics and other clinical indicators.

        In addition, even among pediatric brain tumor patients who survive more than 5 years, late death occurs in 15-25%. Late deaths are mainly due to tumor recurrence or progression, but also partly due to secondary tumors or other secondary diseases.

 

Follow-up & Review

 

        At the end of treatment, children with brain tumors need to be followed up to detect recurrence of the tumor and to manage side effects to promote the overall health of the child. Lifelong follow-up is recommended for all children treated for brain tumors because of the potential for late recurrence.

1. Review

        At the follow-up visit, the doctor will ask about the patient's symptoms and perform an examination, and may perform laboratory tests or imaging tests, such as an MRI scan, in order to determine whether the tumor has progressed or recurred, and to monitor for side effects. The specific follow-up plan for the review will be determined by the type of tumor, its stage, where it occurs, and the treatment the patient has received.

        Because childhood brain tumor survivors are at risk for developing secondary tumors, your doctor may recommend necessary cancer screenings depending on your child's age and the treatment he or she is receiving.

 

Routine

1. Daily life management

1) Diet

        Care should be taken to provide patients with a nutritious and balanced diet, guaranteeing the intake of high-quality proteins (e.g. meat, eggs, milk, poultry, fish and shrimp, soybeans and soybean products, etc.), as well as more grains and cereals, vegetables and fruits, and dairy products and nuts in moderation, in order to ensure the intake of other nutrients. Clinical dietitians in the nutrition department of the hospital can be consulted to provide appropriate nutritional programs for patients. If weight loss is severe, nutritional support through tube feeding or parenteral nutrition may be considered.

        Meanwhile, there is no evidence that children with brain tumors need to take nutraceuticals (e.g., vitamins, herbs, and other nutraceuticals), or that any nutraceuticals significantly reduce the risk of brain tumor progression or recurrence. In addition, since nutraceuticals are not required to undergo clinical trials to ensure safety and efficacy before they are marketed as drugs are, it is advisable to consult your child's supervising physician if you wish to take nutraceuticals in order to confirm their safety and to ensure that they will not interact with therapeutic medications.

2) Rest and exercise

        The patient needs to be guaranteed a sleep schedule. Regular and quality sleep is helpful for recovery and immunity. A suitable sleep environment (usually dimly lit, quiet, and at the right temperature) may be helpful in improving the patient's quality of sleep.

        If the patient's physical condition permits, you can encourage and assist the patient to perform some simple activities. Moderate exercise is helpful in preventing muscle atrophy, enhancing physical strength and endurance, and promoting appetite.

3) Life Habits

        If the patient has neutropenia caused by treatment, attention should be paid to preventing infections. It is important to pay attention to personal and living environment hygiene, do not approach patients with infectious diseases, and do not go to crowded places.

        If the treatment causes thrombocytopenia, care needs to be taken to avoid bleeding by staying away from sharp, prickly toys and objects, as well as avoiding impact-intensive sports (e.g., bouncing, soccer, basketball, etc.).

2. Daily condition monitoring

        Post-operative complications, chemotherapy-induced side effects (e.g., hair loss, fatigue, vomiting, etc.), recurrence of tumor metastasis, and growth and development problems need to be addressed. Consult your doctor when fever, worsening of symptoms, new symptoms, and treatment-induced side effects occur.

3. Special Precautions

        Children with brain tumors treated with radiotherapy have a risk of long-term side effects and secondary tumors, which may develop many years after the end of treatment, and which are related to the regimen and dose of treatment. Therefore, it is important to keep a record of all the patient's visits and treatments for future review and reference.

4. Prevention

        There is no better way to prevent brain tumors in children because the exact cause of brain tumors in children is not known.

        For children, care should be taken to avoid unnecessary ionizing radiation, which may increase the risk of brain tumors. If they have to receive radiation because of treatment for other diseases, it is important to pay attention to Follow-up & Review afterwards, watch out for symptoms related to brain tumors in children, and seek medical attention if any abnormality occurs.

        For families with genetic disorders associated with childhood brain tumors, it is also important to pay special attention to the symptoms associated with childhood brain tumors and bring your children for relevant examinations in a timely manner.

        Meanwhile, for pediatric brain tumor patients, regular follow-up and maintaining good healthy lifestyle habits can help prevent and detect early recurrence of the disease or the emergence of distant effects.

 

Cutting-edge Therapeutic & Clinical Research

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References

 

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Audit specialists

Tian Yongji, Deputy Director of Pediatric Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

Personal: https://baike.baidu.com/item/%E7%94%B0%E6%B0%B8%E5%90%89/20785314?fr=aladdin