Intracranial metastatic tumor
Intracranial metastatic tumors are malignant tumors from other parts of the body that have metastasized 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 will die rapidly. In recent years, due to the improvement of diagnostic techniques and the adoption of comprehensive treatment for malignant tumors, the cure rate and remission rate of extracranial primary tumors have increased significantly, but the incidence and lethality of intracranial metastatic tumors are still high. Therefore, it is important to improve the understanding of this disease and to provide timely and effective diagnosis and treatment.
1.Epidemiology
The incidence of intracranial metastatic tumors is now generally estimated to be 20% to 40%. Among various tumors, lung cancer, gastrointestinal cancer and breast cancer have the highest number of deaths and intracranial metastases, and the probability of intracranial metastases for each tumor is melanoma, breast cancer and lung cancer in order. As with systemic cancers, intracranial metastases are more likely to occur between the ages of 40 and 60, accounting for about 2/3 of the cases. intracranial metastases in children are different from those in adults, and the intracranial metastasis rate of solid tumors is only 1/4 to 1/2 of that in adults. primary tumors prone to intracranial metastases are leukemia, lymphoma, and osteogenic tumors, in that order.
2. Pathogenesis
2.1. Metastasis pathway: mainly direct infiltration and blood metastasis.
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 penetrate into the brain parenchyma through the perivascular space in the brain;
②Blood metastasis: Most of the tumor cells metastasize to the brain through the blood route, most of them through the arterial system, and a few tumors may metastasize to the skull through the vertebral vein system (Batson’s plexus);
(iii) 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 metastases may occur.
2.2. Pathological features: the distribution of metastases in the brain is related to the anatomical features of cerebral blood vessels. Because the cerebral blood vessels suddenly become thin at the junction of gray and white matter in the brain, which prevents 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. According to the number of metastases, they can be divided into single, multiple and diffuse; about 70% to 80% of brain metastases cases are found to be multiple.
3. Clinical manifestations
3.1. 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 about 21.4%, that is, after a period of remission after acute onset, intracranial occupancy symptoms come back and progressive aggravation, the remission period can be weeks to years; progressive aggravation accounts for about 32%, acute or chronic The onset of the disease and progressive exacerbation, lasting 3 to 4 months.
3.2. 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 while the primary symptoms are absent or not obvious.
Headache is the most common symptom and the early symptom in most patients. It starts with limited headache, mostly on the side of the lesion, and later develops into 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.
②Common neurological signs: Depending on the location of the brain metastases and the number of lesions, different signs may appear. Most of the localized signs appear several days to weeks after the onset of headache and other symptoms of cranial hypertension.
(iii) Psychiatric symptoms: seen in 1/5 to 2/3 of patients, especially in frontal lobe and diffuse meningeal metastases, which may be the first symptoms.
④Membrane irritation sign: It is mostly seen in patients with diffuse brain metastases, especially those with meningeal metastases and ventricular metastases. Sometimes, meningeal irritation signs may also appear due to bleeding from metastases or combined inflammatory reactions.
(5) 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. The focal epilepsy that appears early has localization significance. Focal epilepsy can be continuous, and some patients show generalized tonic-clonic seizures as the disease progresses.
(6) Others: generalized weakness and cancer fever are the late manifestations of the disease, which are seen in 1/4 of patients and soon accompanied by impaired consciousness.
4. Laboratory and special tests
4.1. 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, which can show small metastases, meningeal metastases, metastases in the cerebellum and brain stem that are difficult to be detected by CT, MRI has been used as the preferred examination. The MRI signal of brain metastases is non-specific, mostly low signal on T1-weighted imaging and high signal on 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 in which cancer cells are found in the cerebrospinal fluid, spinal cord or spinal nerve root dissemination is seen in approximately 38% of patients on MRI.
4.2. Computed tomography (CT): Currently, CT is often considered when MRI equipment is not available or when the patient is contraindicated to undergo MRI (pacemaker or other magnetic implants in the body). Whole-body CT can detect the primary tumor and other extracranial metastases.
4.3. Stereotactic aspiration biopsy: For those who cannot be clearly diagnosed by MRI and CT examination, stereotactic biopsy is feasible.
5. Diagnosis and differential diagnosis
5.1. Diagnostic basis: The clinical manifestations of brain metastases are very similar to primary brain tumors, but brain metastases should be suspected if
①Age older than 40 years old, with a history of smoking;
(ii) The disease has a remission phase;
③History of systemic tumor;
④ symptomatic epilepsy with wasting or the presence of rapidly developing limb weakness. For patients with suspected brain metastases, especially those with a history of systemic tumors, cranial MR enhancement scans should be preferred. Combined with the medical history and targeted ancillary tests, the diagnosis is not difficult.
5.2. Differential diagnosis: It must be differentiated from the following diseases.
① primary tumor of the brain.
②Brain abscess.
(iii) cerebral infarction or cerebral hemorrhage.
④Cerebral cysticercosis.
5.3. single or multiple brain metastases? This is important for the choice of treatment. Multiple brain metastases are most often indicated by the following conditions.
(1) Rapid onset and short duration of disease;
(2) Poor systemic condition, with malignant mass;
③The clinical manifestations are extensive and complex and cannot be explained by a single lesion;
④Headache is inconsistent with other manifestations of cranial hypertension;
⑤ Psychiatric symptoms are obvious and appear early. 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 carefully made, and necessary differential diagnosis and auxiliary examinations must still be performed, mainly with glioma and brain abscess.
5.4. 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 outside the brain, etc., which can help to select treatment and judge the prognosis.
5.5. 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 radiography 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 for, and abdominal CT, B-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. In female patients, attention should be paid to the examination of the breast.
6.1. Steroid hormone
The main effect is to reduce tumor-induced cerebral white matter edema, reduce cerebral vascular permeability, and a few lesions can be shrunk. In advanced patients or when other palliative therapies are ineffective, steroid hormones not only make patients sensitive to these therapies (e.g. radiotherapy), but also reduce headache, thus prolonging patients’ life and relieving their pain. They can be used alone or in combination with other therapies. Early use is generally advocated, i.e., administration should be started as soon as brain metastases are detected, and dexamethasone is commonly used.
6.2 Surgical procedures
6.2.1. Indications for surgery: Patients with brain metastases with the following conditions can be considered for surgery:
①Single 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, renal cancer) or when the lesions are too large for stereotactic radiosurgery (diameter >3.5 cm);
(3) For multiple brain metastases that are sensitive to radiotherapy and have life-threatening larger tumors, the larger tumors can be removed first and then treated with radiotherapy;
④Difficulty in differential diagnosis with other intracranial lesions (such as meningioma, abscess, hematoma, etc.);
⑤ With life-threatening intracranial hemorrhage;
⑥Symptoms of malignant pain require placement of Ommaya reservoir bursa for intrathecal or intracerebroventricular injection interval then for 6 months. In some cases, resection of brain metastases followed by resection of the primary cancer can also achieve better results.
6.3. conventional radiotherapy
Radiotherapy for brain metastases is controversial. Some retrospective studies have confirmed that surgery + postoperative radiotherapy does not reduce recurrence and prolong survival, while some other studies have come to the opposite conclusion. Currently, radiotherapy is generally considered to be indicated for most patients and is the other commonly used tool after surgery. Indications are.
①Post-operative brain metastases ;
②Tumors sensitive to radiotherapy, such as small cell lung cancer, lymphoma, breast cancer;
③Tumors that are 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, it is no longer advocated to use high-dose radiotherapy regimens, and it is generally advocated to perform fractionated radiotherapy, with the total dose no more than 50 Gy, less than 2 Gy per day, to be completed within 1 month.
6.4. Stereotactic Radiosurgery
Including gamma knife, X-ray knife, particle beam knife, of which gamma knife is more commonly used. Gamma knife has a wide range of indications in the treatment of brain metastases, and in recent years, there is an increasing trend of using radiosurgery to treat brain metastases, and it may even replace surgery for small single brain metastases. However, for larger brain metastases (>3.5cm in diameter) with obvious occupying signs or bleeding, surgery should still be preferred. The local control rate of gamma knife treatment for brain metastases is 80% to 90%, and the average survival time is 8 to 11 months. For single brain metastases, the treatment effect is similar to surgery + whole brain radiotherapy. As with surgery, gamma knife does not prevent the emergence of new intracranial metastases, so some advocate supplementing gamma knife surgery with 20-30 Gy of whole brain radiotherapy.
6.5. Chemotherapy
The notion that chemotherapy is ineffective for brain metastases has been recently shaken by new research findings. Chemotherapy is now considered appropriate for the following brain metastases, especially when combined with surgery or radiation therapy: 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, and adriamycin. Recently, the new second-generation alkylating agent-imidazolotetrazine derivative temozolomide (domestic trade name Tiqing) is used for the treatment of brain metastases, which is rapidly absorbed after oral administration and has nearly 100% bioavailability and broad-spectrum antitumor activity, but the efficacy is to be evaluated.
6.6. Interstitial Brachytherapy
As an adjuvant therapy, it is often considered after the lesion is unresectable or has received the maximum dose of radiotherapy. The treatment is achieved by implanting radioactive substances and chemicals directly into the metastases by stereotactic methods or intraoperatively, so that a higher therapeutic concentration is obtained inside the tumor, while the normal tissues around the tumor are rarely affected.
6.7. 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, aggressive treatment is advocated. Stereotactic radiosurgery is commonly used in the treatment of recurrent brain metastases, and most lesions can be controlled. For single recurrent brain metastases whose systemic tumor has been controlled, surgery is still an option.
7.Prognosis
The prognosis of brain metastases is poor. Some data show that the average survival time of incurable patients is 4 weeks, and most patients die from brain herniation and brainstem compression caused by cranial hypertension. There are many factors that affect the survival of patients with brain metastases, the main ones are.
① Systemic condition;
②The presence of extracranial metastases from other sites;
③The latent period of brain metastasis;
④Total resection of the lesion is better than partial resection or biopsy;
⑤ Combined treatment is better than one treatment alone;
(6) Treatment of 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, and among lung cancer, undifferentiated and adenocarcinoma are worse than squamous cancer.