Intracranial metastatic tumors refer to malignant tumors from other parts of the body that metastasize into the skull. Although intracranial metastases are not as common as liver and lung metastases, the clinical manifestations of intracranial metastases are obvious and serious, and those who are not treated in a timely manner mostly die rapidly. Therefore, it is important to improve the understanding of this disease for the timely and effective diagnosis and treatment of patients. 1. Epidemiology The incidence of intracranial metastases varies considerably depending on the time period, population and examination methods. With the improvement of diagnostic methods and the increase of human life expectancy, the survival rate of cancer patients has increased, and the incidence of intracranial metastases has also increased accordingly, and the incidence of intracranial metastases is now generally estimated to be 20%-40%. The incidence of intracranial metastases in children is different from that in adults, and the rate of intracranial metastases of solid tumors in children is only 1/4 to 1/2 of that in adults. 2. Pathogenesis (1) Direct infiltration: Primary and secondary tumors in the peripheral tissues of the skull can directly infiltrate and destroy the skull and dura mater, or reach the parenchyma of the external surface of the brain through the pores of the skull base. . After tumor cells invade into the skull, they may spread widely with cerebrospinal fluid in the subarachnoid space or invade into the brain parenchyma through the perivascular space in the brain; ② Blood metastasis: most tumor cells metastasize into the brain through the blood route, most of which are through the arterial system, and a few tumors may metastasize into the skull through the vertebral vein system (Batson’s plexus); ③. Cerebrospinal fluid metastasis and lymphatic metastasis: less common. Some brain and spinal cord tumors, especially ventricular meningioma and poorly differentiated glioma, can spread and implant along the subarachnoid space, which often occurs after tumor resection or biopsy. Malignant tumors in the adjacent parts of the skull may enter the cerebrospinal fluid or vertebral vein plexus through the lymphatic gap around the cranial cavity, and further intracranial metastasis may occur. (2) Pathological characteristics: The distribution of metastases in the brain is related to the anatomical features of cerebral vessels. Because the cerebral blood vessels suddenly become thin at the junction of gray and white matter in the brain, preventing further forward movement of cancer cell emboli, metastases are mostly located at the junction of gray and white matter, and are often located in the junction area of the distribution of large blood vessels in the brain, which is the so-called Watershed area. In addition, the distribution of metastases is related to the volume and blood supply of each partition of the central nervous system, about 80%-85% of metastases are distributed in the cerebral hemisphere, 10%-15% in the cerebellar hemisphere, and about 5% in the brainstem. In addition to the above most common intracerebral metastases, metastases can also be distributed in cranial nerves, large intracerebral vessels, dura mater, venous sinus and intracranial plate. The number of metastases can be classified as solitary, multiple and diffuse. Past studies have found that about 50% of brain metastases are multiple. Recently, due to the use of advanced examination methods such as high-resolution CT and MR, about 70% to 80% of brain metastases cases are found to be multiple. According to the general manifestation, they can be divided into four types: cortical nodules, meningeal cortex, cornu and cranial nerve, among which the latter two types are often accompanied by meningeal metastases. The histological pattern of brain metastases is the same as that of the primary cancer, but sometimes better or worse differentiated than the primary tumor. The histological pattern of the tumor cannot be classified in about 1/3 cases. 3. Clinical manifestations (1) Mode of onset and course of disease: acute progression accounts for 46.6%, often within 1 to 2 days of rapid coma and hemiparesis, progressive deterioration, the course of disease generally does not exceed 2 weeks; intermediate remission accounts for 21.4%, that is, after a period of remission after acute onset, intracranial occupying symptoms come back and progressive aggravation; progressive aggravation accounts for 32%, acute or chronic onset, and is Progressive exacerbation, which lasted for 3-4 months. (2) Symptoms and signs The symptoms of brain metastases are often later than the primary tumor, but some patients can develop symptoms of brain metastases at the same time when the primary tumor is found, and some patients can only see focal symptoms of brain metastases but the primary symptoms are absent or not obvious. Headache is the most common symptom and the early symptom in most patients. It starts as a limited headache, mostly on the side of the lesion, and later develops into a diffuse headache. Due to the rapid development of increased intracranial pressure caused by brain metastases, headache and accompanying intellectual changes and meningeal irritation signs are obvious, while optic nerve papilledema and cranial hypertension changes of the skull are not obvious. Common neurological signs: Depending on the location of the brain metastases and the number of lesions, different signs may appear. Signs and symptoms are not synchronized, and the former often appear later than the latter, with most localized signs appearing days to weeks after the onset of headache and other symptoms of cranial hypertension. Psychiatric symptoms: They are seen in 1/5 to 2/3 of patients, especially in frontal lobe and diffuse meningeal metastases, and may be the first symptoms. Meningeal irritation signs: Most often seen in patients with diffuse brain metastases, especially in meningeal and ventricular metastases. Sometimes meningeal irritation may also occur due to bleeding from the metastases or combined inflammatory response. Epilepsy: Various forms of seizures can occur, with generalized tonic clonic seizures and focal epilepsy prevalent in about 40% of patients, and multiple brain metastases are prone to seizures. Focal epilepsy that appears in early stages has localization significance. Focal epilepsy can be continuous, and some patients show generalized tonic-clonic seizures as the disease progresses. Other: generalized weakness and cancer fever are the late manifestations of the disease, which are seen in 1/4 of the patients and soon accompanied by impaired consciousness. Laboratory and special examinations (1) Magnetic resonance imaging (MRI) of the head: At present, high-resolution MRI and 3rd generation CT can detect tumors ≤5mm in diameter. Due to the advantages of 3D imaging of MRI, it can show small metastases, meningeal metastases, metastases in the cerebellum and brainstem that are difficult to be detected by CT. The MRI signal of brain metastases is non-specific, mostly low signal in T1-weighted imaging and high signal in T2-weighted imaging. Because of the obvious cerebral edema around metastases, small metastases are difficult to show in T1-weighted imaging, but clear in T2-weighted imaging. The detection rate of this disease can be improved after intravenous injection of paramagnetic contrast agent (Gd-DTPA). If there are enhancing nodules in the basal pool, lateral fissure pool, cortical sulcus gyrus and cerebellar curtain, it often suggests meningeal metastases. Double or triple enhancement combined with delayed scanning can detect microtumors of 1 to 2 mm in diameter, thus making the early diagnosis of brain metastases possible. For meningeal metastases with cancer cells found in the cerebrospinal fluid, spinal cord or spinal nerve root dissemination is seen in about 38% of patients on MRI. (2) Computed tomography (CT) scan: Currently, CT scan is often considered when MRI equipment is not available or when the patient is contraindicated to undergo MRI examination (pacemaker or other magnetic implants in the body). Whole-body CT can detect the primary tumor and other extracranial metastases. (3) X-ray examination: cranial X-ray examination can show increased intracranial pressure, which has certain diagnostic value for cranial metastases. For patients suspected of brain metastases, chest X-ray should be done routinely. Generally, the positive rate of chest X-ray is only 25%, and the positive rate of chest X-ray is 75%, therefore, the disease cannot be excluded if the chest X-ray is negative. Similarly, X-ray examinations of the gastrointestinal tract, urinary tract and skeletal system should be performed in some patients. (4) Cerebrospinal fluid examination: It is a major method for the diagnosis of meningeal metastases and should be performed carefully in patients with elevated intracranial pressure after intravenous administration of dehydrating agents. The application values are: (1) to find tumor cells, repeated examination is needed to improve the positive rate (generally 80%); (2) cerebrospinal fluid routine and biochemical abnormalities are seen in most patients, such as leukocytosis, decreased sugar, increased protein, negative bacterial and fungal cultures; (3) cerebrospinal fluid enzymatic examination can be increased in some meningeal metastases, but lacks specificity, such as: β-glucuronidase, carcinoembryonic antigen (4) Chorionic gonadotropin measurement is valuable for the diagnosis of brain metastasis of choriocarcinoma. (5) Stereotactic aspiration biopsy: for those who cannot be clearly diagnosed by the above tests, stereotactic biopsy is feasible. For those who suspect meningeal metastasis, the occipital foramen magnum can be exposed through a small suboccipital incision and the arachnoid membrane of occipital pool can be taken for examination. (6) Nuclear examination: Radionuclide concentration areas can be seen at the site of metastases by nuclear imaging, but the differential diagnosis is not significant. The presence of cranial metastases can be detected by nuclear bone scan. Positron emission tomography (PET) can help to distinguish high and low grade malignant tumors, and also distinguish tumor recurrence from radiation necrosis or postoperative reaction, as well as to detect extracerebral metastases or primary foci. 5. Diagnosis and differential diagnosis (1) Diagnostic basis: The clinical manifestations of brain metastases are very similar to primary brain tumors, but brain metastases should be suspected if the following conditions are present: (1) age older than 40 years old with a history of smoking; (2) a history of remission in the course of the disease; (3) a history of systemic tumors; (4) symptomatic epilepsy with wasting or the appearance of rapidly developing limb weakness. For patients suspected of brain metastases, especially those with a history of systemic tumors, cranial MR enhancement scans should be preferred. The diagnosis is not difficult when combined with the medical history and targeted ancillary tests. (2) Differential diagnosis: ① Primary brain tumor: According to the medical history, it is generally not difficult to differentiate between patients with advanced systemic carcinoma, especially when they present with intracranial occupancy. Benign primary brain tumors have their own characteristics and are easy to differentiate. Malignant glioblastoma, which is sometimes difficult to distinguish from this disease, requires the help of biopsy. Superficial meningeal metastases must be distinguished from small meningiomas, which often have no obvious symptoms or peri-tumor cerebral edema. If there is cranial destruction, it must be distinguished from cranial changes caused by meningioma or extracranial lesions. Brain abscess: It is not difficult to differentiate from brain metastases based on medical history and necessary auxiliary examinations, but in rare cases, brain abscess can occur in cancer patients due to the following factors, which should be noted in the diagnosis: cancer patients are susceptible to bacterial or fungal infections due to their systemic resistance and decreased immune function caused by long-term use of hormones; intracranial or skull base metastases cause intracranial and extracranial traffic due to radiotherapy or surgical treatment, which facilitates bacterial invasion; primary or Those with primary or secondary lung cancer often have bronchial obstruction, causing lung abscess, which leads to brain abscess. (iii) Cerebral infarction or cerebral hemorrhage: autopsy found that 15% of patients with systemic carcinoma were accompanied by cerebrovascular disease, with half of bleeding and half of ischemia, and the cause of bleeding was mostly coagulation mechanism disorder or thrombocytopenia. It is sometimes difficult to distinguish metastases from stroke solely from clinical and CT manifestations, especially for bleeding within metastases, when MR plain plus enhanced examination or surgical removal of hematoma is feasible, the latter not only can save the patient’s life but also can clarify the diagnosis. ④Cerebral cysticercosis: It must be differentiated from multiple brain metastases. Patients with cerebral cysticercosis have a history of exposure to epidemic water. Typical CT and MRI show multiple scattered round or oval, focal cysts of varying sizes in the brain parenchyma, with small nodules within the cysts. The density or signal of the small nodules may be enhanced, or if not enhanced, they are foci of calcification. Mild or no cerebral edema surrounds the lesions. Since serological examination is unreliable, experimental cysticercosis medication can be given to suspected patients and follow-up with CT and MRI can improve the detection rate. (3) Single or multiple brain metastases? This is important for the choice of treatment. Multiple brain metastases are often indicated by the following conditions: (1) rapid onset and short duration of disease; (2) poor general condition with malignant mass; (3) extensive and complex clinical manifestations that cannot be explained by a single lesion; (4) inconsistency between headache and other manifestations of cranial hypertension; (5) obvious psychiatric symptoms and early appearance. Generally speaking, the diagnosis of multiple brain metastases is not difficult, and if multiple brain lesions are found in patients with systemic carcinoma, the diagnosis of brain metastases can mostly be established. In contrast, the diagnosis of solitary brain metastases must be made carefully, and necessary differential diagnosis and auxiliary examinations should still be conducted. (4) Diagnostic points to note: In the diagnosis of brain metastases, attention should also be paid to the distribution of metastases, neurological function status, metastases in other parts of the brain, etc., which can help to select treatment and judge the prognosis. (5) Finding the primary cancer: Since most metastases are transferred to the brain via blood, the lung is an important organ for producing brain metastases. Intrapulmonary lesions can originate in the lung or metastasize to the lung from outside the lung, with lung cancer predominating in male patients and breast cancer in female patients. It has been found that about 60% of patients with brain metastases can be detected by chest imaging. Therefore, careful chest physical examination and chest X-ray or chest CT examination (better than MR examination) are very important to detect the primary cancer. For patients with negative lung examination, primary foci outside the lung should be actively searched, and abdominal CT, ultrasound and whole-body PET examinations are feasible, which can generally detect the primary foci. However, there are still some patients who cannot find the primary foci after repeated systematic examinations. For female patients, attention should be paid to the examination of the breast. 6. Treatment includes steroid hormone, surgery, radiotherapy, stereotactic radiosurgery, intra-tumor therapy and chemotherapy (Table 2-8-13-1). With the continuous development of diagnostic radiology and neurosurgical treatment, the efficacy and prognosis of intracranial metastases have been greatly improved, and the 1-year survival rate after surgery has increased from 14% to 21% to 22% to 31%. The idea of surgery combined with postoperative radiotherapy has been accepted by many people, and the combination therapy has shown promising treatment prospects. (1) Steroid hormone The main effect is to reduce tumor-induced cerebral white matter edema, reduce cerebrovascular permeability, and a few lesions can be shrunk. In advanced patients or when other palliative therapies are ineffective, steroid hormones can not only make patients sensitive to these therapies (e.g. radiotherapy), but also reduce headache, thus prolonging patients’ lives and alleviating their pain. They can be used alone or in combination with other therapies, and their early use is generally advocated, i.e., they should be started as soon as a brain metastasis is detected. Dexamethasone is commonly used, but other steroid hormones can also be used, with the effect showing up 6 to 24 hours after the first dose, and the maximum effect reaching 3 to 7 days. Generally speaking, the average survival of patients treated with hormone alone is 2 months. If the disease is stable after treatment, discontinuation is considered, and discontinuation should be carried out slowly over several weeks, and the lowest effective dose should continue to be given to those who cannot tolerate it. (2) Surgery Indications for surgery: Patients with the following conditions can be considered for surgery: (1) single brain metastases located at operable sites; (2) multiple brain metastases located at operable sites, especially when they are not sensitive to radiotherapy or chemotherapy (e.g. melanoma, kidney cancer) or the lesions are too large for stereotactic radiosurgery (diameter >3.5 cm); (3) multiple brain metastases that are sensitive to radiotherapy. Among metastases, there are life-threatening larger tumors, which can be removed before radiotherapy; ④difficulty in differential diagnosis with other intracranial lesions (such as meningioma, abscess, hematoma, etc.); ⑤with life-threatening intracranial hemorrhage; ⑥with symptoms of malignant pain, Ommaya reservoir should be placed for intrathecal or intracerebroventricular injection of chemotherapeutic drugs or opiates; ⑦with hydrocephalus, shunt surgery is required. Surgical efficacy: Since most brain metastases are superficially located and not rich in blood supply, they can be easily removed, especially with the use of microsurgical techniques, laser, ultrasonic shock-absorbing system (CUSA), stereotactic and neuronavigation devices, total excision of the tumor is not difficult and generally does not increase postoperative neurological dysfunction, thus creating the necessary conditions for other postoperative treatments. (3) Conventional Radiotherapy There are many controversies regarding the radiotherapy of brain metastases. One part of the retrospective study confirmed that surgery + postoperative radiotherapy did not reduce recurrence and prolong survival, while another part of the study came to the opposite conclusion. Currently, radiotherapy is generally considered to be indicated for most patients and is the other commonly used treatment after surgery. The indications are: (1) postoperative brain metastases; (2) tumors sensitive to radiotherapy, such as small cell lung cancer, lymphoma, and breast cancer; and (3) tumors less sensitive to radiotherapy, such as non-small cell lung cancer, adrenal tumors, and malignant melanoma. The most commonly used radiotherapy is whole brain radiotherapy, but some people also advocate local radiotherapy. Since radiotherapy can cause early (occurring within a few days after the start of radiotherapy, such as headache, nausea, vomiting, fever, etc.) and late (such as dementia, ataxia, etc.) radiation reactions, the use of high-dose radiotherapy regimens has been discouraged, and it is generally advocated to perform fractionated radiotherapy with a total dose of no more than 50 Gy and less than 2 Gy per day, to be completed within 1 month. The single high-dose regimen has been gradually rejected. Recent studies have found that peritumor cells are sensitive to radiotherapy, while cells in the tumor core area are insensitive to radiation due to hypoxia, and the use of radiotherapy booster can increase the sensitivity of hypoxic cells to radiation, thus improving the therapeutic effect. Radiotherapy by itself can prolong the average survival time of patients with brain metastases, and it is more effective when combined with hormone and other treatments. Good radiotherapy results are often associated with the following factors: ① KPS (Karnofsky Performance Scale) ≥ 70%; ② no primary tumor is found or has been controlled; ③ patient age 3.5 cm), with obvious occupancy signs or bleeding, surgery should still be preferred. The local control rate of gamma knife treatment for brain metastases is 80%-90%, and the average survival time is 8-11 months. For single brain metastases, the treatment effect is similar to surgery + whole brain radiotherapy. (4) Chemotherapy The concept that chemotherapy is ineffective for brain metastases has been shaken by new research results in the past. The following brain metastases are now considered suitable for chemotherapy, especially when combined with surgery or radiotherapy: germ cell tumors, small cell lung cancer, some breast cancers, lymphomas, and malignant melanoma. Conventional routes of administration are often ineffective and require administration via the carotid or vertebral artery to improve efficacy and reduce systemic toxic effects. Commonly used drugs include VM26, BCNU, cis-chloroplatinum, adriamycin, etc. (5) Interstitial brachytherapy is often considered as an adjuvant treatment after the lesion is unresectable or has received the maximum dose of radiotherapy. By implanting radioactive substances and chemicals directly into the metastases through stereotactic methods or intraoperatively, a higher therapeutic concentration is obtained inside the tumor, while the normal tissues around the tumor are rarely affected, thus achieving the treatment purpose. (6) Treatment of recurrent brain metastases Recurrence of brain metastases is often a sign of deterioration of the disease, which is difficult to treat and generally has a poor prognosis. Nevertheless, many scholars still advocate active treatment, and believe that any treatment that has been used at the beginning can be used again this time, only that it needs to be selected and adjusted accordingly and reasonably according to the specific situation of the patient. General radiotherapy is often chosen, sometimes it may be the only means, and since most patients have already received radiotherapy, the dose should be reduced, generally 15-25 Gy, but whether this dose is effective is still controversial. Stereotactic radiosurgery is also commonly used in the treatment of recurrent brain metastases, and most of the lesions can be controlled. 7.Prognosis The prognosis of brain metastases is poor. Some data show that the average survival time of untreated patients is 4 weeks, and most patients die from brain herniation and brainstem compression caused by cranial hypertension. There are many factors affecting the survival of patients with brain metastases, mainly: (1) the general condition; (2) whether there are metastases from other parts outside the skull; (3) the latent period of brain metastases; (4) the total excision of the lesion is better than partial excision or biopsy; (5) the combined treatment is better than one treatment alone; (6) the treatment of the primary tumor; (7) the pathological nature of the tumor, the survival period of brain metastases from non-lung cancer (breast cancer, thyroid cancer, ovarian cancer, kidney cancer, melanoma) is longer than that of brain metastases from lung cancer. Among lung cancers, undifferentiated carcinoma and adenocarcinoma are worse than squamous carcinoma.