Approach to the patient with leptomeningeal metastases

Introduction

Leptomeningeal spread occurs in both solid tumors and hematologic malignancies. Leptomeningeal disease (LMD) for all primary cancer types portends a very poor prognosis, with survival measured in weeks if left untreated and an average of only 3.5 months with maximal therapy. The gold standard for diagnosing LMD is the presence of malignant cells observed on cerebrospinal fluid (CSF) cytology, though in a patient with known malignancy supportive radiologic findings in the setting of new neurological signs and symptoms is highly suggestive. Treatment is individualized based on various factors including the patient’s performance status, the type and status of systemic cancer, burden of LMD, and clinical symptoms. Management is best conducted by a multidisciplinary team with involvement of palliative care for symptom management, radiation oncology, hematology or oncology, neuro-oncology, neurology, and neurosurgery. In this chapter we begin with a review of the common clinical principles for understanding LMD, including the clinical presentation, diagnostic tools, and therapeutic options. We then provide a case-based review with three cases (Cases 15.1–15.3) that focus on the approach to diagnosing LMD and two cases (Cases 15.4 and 15.5) that highlight the approach to treatment.

General principles for understanding leptomeningeal disease

Central nervous system (CNS) metastases from systemic cancers involve metastases to the brain parenchyma, dura, and leptomeninges (pia, subarachnoid space, and arachnoid mater). LMD is also known as neoplastic meningitis and carcinomatous meningitis. Leptomeningeal spread occurs in both solid tumors and hematologic malignancies via hematogenous dissemination, direct extension from solid brain lesions, as well as endoneural, perineural, and perivascular spread.

Common solid tumors that metastasize to the leptomeninges include melanoma, breast cancer, small-cell lung cancer, and non–small-cell lung cancer. ^, Higher prevalence is seen in breast cancer, followed by lung cancer and melanoma. In patients with breast cancer, HER2-positive and triple-negative breast cancers are associated with increased risk of CNS metastases including both brain parenchymal disease and LMD. ^, LMD occurs in 10–30% of acute leukemias (acute myelogenous leukemia more than acute lymphoblastic leukemia at diagnosis) and is rare in chronic leukemias. It is more common in non-Hodgkin’s lymphoma (5–30%; 5% in diffuse large B-cell and peripheral T-cell lymphoma and 24% in Burkitt and lymphoblastic leukemia) and is rare in Hodgkin’s lymphoma. ^, Median time from systemic cancer diagnosis to the diagnosis of LMD ranges from 11 months in hematologic malignancies to 2 years in solid tumors. ^,

The diagnosis of LMD for all primary cancer types portends a very poor prognosis with average survival of 4–6 weeks post diagnosis if left untreated and an average of 3.5 months if treated. In those with breast cancer, patients with triple-negative breast cancer have the poorest survival, HER2-positive patients have the longest survival, and hormone receptor–positive patients have the longest time to the development of LMD. ^{, ,} A multidisciplinary approach to management is optimal with involvement of palliative care for symptom management, radiation oncology, and hemato-oncology in conjunction with neuro-oncology for systemic and intra-CSF therapies, and neurosurgery for placement of Ommaya and ventriculoperitoneal (VP) shunt when appropriate.

Patient presentation

LMD can clinically manifest in a variety of ways including focal neurologic symptoms and generalized neurologic decline from hydrocephalus as well as cranial nerve and spinal nerve findings. These various clinical manifestations occur from tumor infiltration of the leptomeninges, cranial nerves, spinal nerves, and cortical surfaces.

Infiltration of leptomeninges with cancer cells can cause clogging of arachnoid granulations causing increased intracranial pressure (ICP) and hydrocephalus. This can lead to morning headaches, nausea, vision decline, cranial nerve palsy, unsteadiness of gait, urinary incontinence, and even mental status changes. There can also be dysfunction from cortical irritation particularly in the setting of bulky or nodular disease-causing seizures, headache, and encephalopathy.

Focal symptoms occur with involvement of different areas of the neuro-axis. Tumor cells can invade spinal and cranial nerves (CN) passing through the subarachnoid space, at first producing demyelination and finally destroying the axons of those nerves. Involvement of CN causes ptosis, extra-ocular movement abnormalities, diplopia, facial droop, changes in facial sensation, difficulty swallowing, dysarthria, and hearing difficulty. Multiple CN deficits without crossed motor or sensory deficits suggests involvement of the subarachnoid space. The ventral root containing the motor axons and the dorsal root containing the sensory axons exit the spinal cord into the subarachnoid space to form spinal nerves. Spinal nerves then enter the neural foramen and exit the vertebral column. Infiltration of the nerve roots and spinal nerves causes lower motor weakness, hypoesthesia, paresthesia, and neuropathic pain, as well as cauda equina syndrome (saddle anesthesia, urinary incontinence, fecal incontinence and constipation from parasympathetic denervation of the rectum, and sigmoid and anal sphincters). ^,

Diagnosis

Per National Comprehensive Cancer Network (NCCN) guidelines, LMD can be diagnosed in patients who have: (1) CSF cytology showing malignant cells; (2) positive radiologic findings with supportive clinical findings or signs and symptoms suggestive of CSF involvement in a patient with known malignancy.

Approach to Diagnosis . Clinical symptoms and signs are critical for recognizing involvement of the leptomeningeal compartment. Clinicians should have a high suspicion for the possibility of leptomeningeal dissemination in a patient with metastatic cancer and should prompt further workup. LMD can be diagnosed in asymptomatic patients who are diagnosed incidentally during follow-up staging imaging. When evaluating a patient with possible leptomeningeal disease, clinicians should consider the following:

• 1.

  Symptomatic versus asymptomatic disease: is the patient symptomatic for LMD or asymptomatic?

• 2.

  Burden of disease: is there diffuse leptomeningeal involvement or focal disease?

• 3.

  Bulky disease: is there bulky, nodular disease (e.g., >2 mm thickness on imaging) or non-bulky disease?

• 4.

  Location of leptomeningeal metastasis: is there cranial disease, spinal disease, or a combination?

• 5.

  State of systemic disease: is there progressive systemic disease, controlled systemic disease on treatment, or no evidence of systemic disease?

• 6.

  CSF flow: is there patency of CSF flow to ensure uniform distribution of intrathecal chemotherapy?

Diagnostic tests . Workup of LMD may include the following investigations: (1) CSF sampling (gold standard) with at least CSF cell count, glucose, protein, cytology, and, in hematologic malignancies, CSF flow cytometry; (2) neuroimaging with MRI Brain and total spine with and without contrast or CT Brain and Spine with and without contrast if MRI is contraindicated; (3) CSF flow study via radionuclide cisternogram; and/or (4) CT or PET for systemic staging.

Treatment

The following treatment modalities may be used either alone or in combination and are reviewed further in the following cases.

• 1.

  Radiation therapy (e.g., stereotactic radiosurgery, conventional fractionated radiation therapy, or whole brain radiation therapy)

• 2.

  Systemic therapy (e.g., chemotherapy, targeted treatment, and immunotherapy)

• 3.

  Intrathecal therapy (e.g., Ommaya placement and intrathecal agents)

Clinical cases