I. What is soft meningeal metastatic cancer?
Soft meningeal metastasis is a serious complication of systemic cancer, with high morbidity and mortality. Its primary foci are mostly lung cancer, breast cancer, hematologic malignancies and primary tumors of the central nervous system. Tumor cells invade the soft meninges and grow diffusely or multiply with the cerebrospinal fluid circulation. The diagnosis mainly relies on medical history, clinical manifestations, imaging examination and cerebrospinal fluid analysis. The main treatment strategies include intrathecal or systemic chemotherapy, radiation therapy, surgery and other palliative treatments, and now new therapies such as new chemotherapeutic drugs and immunotherapy are expected to bring new hope for improving the prognosis of LM.
What diseases are most likely to cause soft meningeal metastatic carcinoma?
Soft meningeal metastases usually occur in the late stage of tumor disease, often with metastases from other systems or brain parenchyma.
Solid tumors, hematologic malignancies and intracranial primary malignancies can all have soft meningeal metastasis rate, especially leukemia, lymphoma (such as aggressive non-Hodgkin’s lymphoma), multiple myeloma, breast cancer (especially those over-expressing HER2 gene), lung cancer and melanoma are common with soft meningeal metastasis.
Among primary intracranial malignancies, the risk of soft meningeal metastases is higher in medulloblastoma, retinoblastoma, and supratentorial primitive neuroectodermal tumors, such as up to 30% soft meningeal metastases in medulloblastoma. In addition, non-germ cell germ cell tumors such as ovarian endodermal sinus tumors, embryonal tumors and choriocarcinoma also have a higher risk of meningeal dissemination.
What are the manifestations of soft meningeal metastases?
Since soft meningeal metastases are mainly diffuse lesions, their clinical manifestations lack specificity and often coexist with multiple neurological localization symptoms and signs. In general, headache, diplopia and muscle weakness are the most common neurological symptoms, while delirium, actinic nerve palsy and bilateral physiological reflex asymmetry are the most common neurological signs.
Depending on the location of the soft meningeal metastases, the clinical manifestations can be mainly.
(1) Cerebral hemisphere-related symptoms are seen in about half of the patients, with hydrocephalus and high cranial pressure as the main manifestations. Patients may present with headache, nausea and vomiting, and even gait instability, cognitive impairment, and confusion; those with combined brain parenchymal involvement may also present with seizures, mild hemiparesis, or other neurological localization signs.
(2) Symptoms of cranial nerve involvement are seen in about half of the patients, with cranial nerve involvement of the third, fourth and sixth cranial nerves being the most common, followed by the seventh and eighth cranial nerves. Therefore, diplopia may occur as the main manifestation of cranial nerve involvement, and some of them may show acute blindness due to optic nerve involvement. If patients with tumor develop progressive hearing loss and loss of balance, they should be alerted to the possibility of soft meningeal metastasis in the pontocerebellar horn.
(3) Spinal cord or spinal nerve root involvement is seen in about 3/4 of the patients, often with radiating pain, weakness, numbness, bilateral asymmetry of tendon reflexes and dysfunction of the bowels in the corresponding area.
(3) Meningeal irritation signs are seen in about 15% of patients, which may manifest as cervical tonicity and positive Kernig’s sign.
What tests can confirm the diagnosis of soft meningeal metastatic cancer?
1. Enhanced CT can reveal linear/nodular enhancement of meninges, cerebral pool obstruction and cerebral edema in about 25-50% of soft meningeal metastases.
2. MRI shows diffuse soft meningeal enhancement; nodular occupying lesions can be seen in the subarachnoid space, especially in the brain pool and brain fissure; spinal cord involvement can show linear enhancement of the whole spinal cord or segmental spinal cord, linear or nodular enhancement of cauda equina nerve roots. Among them, the abnormal thickening of cranial nerves, nodular lesions of cauda equina and diffuse thickening of brain and spinal cord surfaces with enhancement have higher specificity.
Cerebrospinal fluid cytology to find malignant tumor cells is the gold standard for the diagnosis of LM. Cerebrospinal fluid pressure, cell count, protein and sugar concentration, tumor marker levels (e.g., β2 microglobulin associated with lymphatic system malignancies, CA125 associated with ovarian cancer, CA15-3 associated with breast cancer, PSA associated with prostate cancer, β- hCG, carcinoembryonic antigen (CEA) associated with colorectal tumors and other solid tumors) are useful for diagnosis.
4. Radionuclide examination of cerebrospinal fluid circulation can detect microscopic lesions that cannot be shown by conventional imaging examination.
V. How to treat soft meningeal metastatic cancer? Is there any hope?
Given that it is not yet possible to completely eradicate the tumor cells in the subarachnoid space, the treatment of LM is palliative in nature. The purpose of treatment is to relieve symptoms, improve and stabilize neurological function, and prolong survival period. The main methods are surgery, radiotherapy and chemotherapy, and individualized treatment plans should be developed according to the patient’s condition.
Surgery: Since LM is widely distributed along the subarachnoid space and cannot be resected radically, the main surgical treatment methods are: subcutaneous burial of ventricular fluid reservoir for repeated intrathecal injection of chemotherapy drugs; ventriculo-abdominal shunt for patients with hydrocephalus and high cranial pressure who have obvious symptoms and are insensitive to glucocorticoid therapy, but there is a risk of tumor dissemination to the abdominal cavity, so systemic chemotherapy is often required.
2. Radiotherapy
(1) The purpose of local radiation therapy is to reduce the neurological localization symptoms caused by isolated lesions and to improve cerebrospinal fluid circulation for subsequent intrathecal chemotherapy. Local radiation therapy should be started as soon as neurological dysfunction occurs, lumbosacral radiation therapy for those with cauda equina symptoms, and skull base radiation therapy for those with cranial neuropathy.
(2) Whole brain radiation therapy is the most commonly used radiotherapy method, and its acute complications mainly include myelosuppression, mucositis and esophagitis; long-term complications include neuropsychological disorders and cerebral leukomalacia.
(3) Whole brain and whole spinal cord radiation therapy is the preferred treatment option for soft meningeal metastases before the advent of intrathecal chemotherapy, but its application is limited because it often causes significant bone marrow suppression and the patient’s tolerance and cooperation are poor.
3. Chemotherapy
(1) Intrathecal chemotherapy is the main treatment modality for soft meningeal metastases, with methotrexate, acephalosporin and cetapide being the most commonly used intrathecal chemotherapeutic agents, and it is generally not necessary to adjust the dose according to body weight and surface area. For those with normal cerebrospinal fluid circulation, intrathecal chemotherapy is usually administered twice weekly for 4-6 weeks.
(2) The combination of systemic chemotherapy and intrathecal chemotherapy can significantly prolong the mean survival of patients, with lipid-soluble chemotherapeutic agents that can cross the normal blood-brain barrier (e.g., cetepe) or drugs that are safer to administer in high doses (e.g., methotrexate or cytarabine) being the preferred choice.
(3) Complications of chemotherapy
(1) Aseptic meningitis, mainly manifested as sudden onset of headache, nausea, vomiting and fever a few hours after intrathecal drug injection, which can last for 12 to 72 hours. Short-term oral or intrathecal steroid injection can prevent its occurrence.
② Delayed cerebral white matter lesions are the most serious complication of chemotherapy, manifesting as apathy, memory loss, altered mental status and ataxia, and can occur after whole brain radiation therapy alone or intrathecal chemotherapy alone
(iii) Acute systemic toxic reactions to chemotherapeutic agents.
4. Immunotherapy: such as cytokines (interleukin-2 and alpha-interferon, etc.) intrathecal injection, monoclonal antibodies, etc.
5. Symptomatic treatment
(1) Glucocorticoids to reduce neuroedema to relieve headache and nerve root pain
(2) Prophylactic application of antiepileptic drugs for those with seizures
VI. Prognosis
LM is a serious complication of systemic cancer with poor clinical prognosis. The long-term remission rate of LM is very low, and most patients die due to the progression of neurological metastases.