Case. A 49-year-old female with history of progressive metastatic epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC) received three lines of treatment with carboplatin, pemetrexed, afatinib, and osimertinib as well as radiation to symptomatic bony metastases. Three years after diagnosis she presented with progressive lower extremity weakness and numbness of 4 weeks, duration followed by urinary and fecal incontinence for 2 weeks. Neurological examination showed 3+/5 strength in bilateral lower extremities, saddle anesthesia, decreased proprioception, allodynia in bilateral lower extremities, hyporeflexia, and decreased rectal tone. MRI Brain and Spine did not reveal evidence of LMD. Initial lumbar puncture was performed with negative CSF cytology. Repeat CSF sampling showed elevated protein at 65 mg/dL, normal glucose, mild leukocytosis (largely lymphocytosis), and CSF cytology was positive for malignant cells.

Teaching Points: Serial Spinal Taps May Be Needed in Highly Suspected Cases Where Initial CSF Cytology Is Negative. This case highlights the importance of serial CSF sampling in patients with high suspicion of disease but negative initial CSF cytology. As was the case for this patient, a negative MRI and a single negative cytology does not rule out LMD. CSF testing is the gold standard for diagnosing LMD. CSF cytology helps establish the diagnosis and monitor treatment response. CSF sampling should include measurement of the opening pressure, cell count, protein, and glucose. CSF cytology should be performed to assess for malignant cells, and flow cytometry should be included when evaluating patients with known or suspected hematologic malignancies. Indicators of CSF involvement include elevated opening pressure and elevated protein.

In patients where there is high clinical suspicion for LMD based on clinical signs and symptoms, a second CSF analysis or third CSF sample may be needed to confirm the diagnosis. Shedding of malignant cells into the CSF likely occurs intermittently, and thus there is a high false-negative rate with initial CSF sampling in patients with active leptomeningeal dissemination. Prior studies suggest that, in patients with active LMD, CSF cytology will be positive in 45% of patients with first spinal tap. This increases to 86% with the second and >90% with third. Factors that increase the diagnostic yield include the volume of CSF sampled, speed of processing CSF for cytology, obtaining CSF in close proximity to a site of active disease, and increasing the number of spinal taps. To increase the diagnostic yield, at least 10.5 mL is generally recommended to be sent for CSF cytology, as the likelihood of capturing malignant cells increases with higher volume. CSF should be processed immediately to reduce cell death. Delay in CSF processing results in 50% of the cells being viable after 30 minutes and only 10% after 90 minutes. Clinicians should be aware that sampling from lumbar dural puncture is more likely to be positive in patients with spinal than intracranial disease. These patients may need repeat sampling.

Case. A 67-year-old male with a 1-year history of progressive anemia and drenching night sweats underwent further workup that revealed abdominal lymphadenopathy. Laparoscopic biopsy of an abdominal lymph node revealed marginal zone lymphoma. Bone marrow biopsy showed bone marrow involvement. He was treated with six cycles of bendamustine and rituximab, followed by maintenance rituximab, which he self-discontinued after a year. Five years after his diagnosis, he developed recurrence of symptoms including night sweats, fatigue, and weight loss. Work-up including repeat bone marrow biopsy revealed recurrent marginal zone lymphoma, and PET-CT showed positive paratracheal lymphadenopathy with minimal bone marrow involvement. He was re-challenged with rituximab monotherapy and, after 2 months of treatment, developed new-onset headaches and suffered a seizure. Neuroimaging with MRI Brain and Total Spine showed no evidence of CNS metastases. Lumbar puncture was performed, showing CSF leukocytosis at 44/UL (85% lymphocytes), protein 284 mg/dL, glucose 40 mg/dL. Flow cytometry with immunophenotyping revealed predominantly T cells and a small population of kappa-restricted CD5-, CD10-, CD20+ B cells (3.2% of total cellular events) consistent with low-level involvement by the patient’s previously diagnosed lymphoplasmacytic lymphoma. Cytology was negative for malignancy. The patient underwent Ommaya placement, and intrathecal chemotherapy was initiated with thiotepa as well as high-dose methotrexate (HD-MTX) and systemic ibrutinib. He had clearance of CSF after four rounds of intrathecal chemotherapy. After 2 months, thiotepa was switched to intrathecal MTX monotherapy due to toxicity. He developed encephalopathy after two doses of intrathecal MTX, and intrathecal therapy was discontinued. He continues to have good performance status 7 months after diagnosis of LMD.

Teaching Points: Flow Cytometry Should Be Included in CSF Sampling for Patients With Hematologic Malignancies. This case demonstrates the role of CSF flow cytometry in evaluating LMD for patients with hematologic malignancies. For hematologic malignancies, flow cytometry is more sensitive than cytology. CSF studies in patients with LMD from any cancer frequently show lymphocytic pleocytosis with increased protein and, in more severe cases, hypoglycorrhachia (i.e., reduced CSF glucose). The differential diagnosis of hypoglycorrhachia includes neoplastic meningitis, bacterial or fungal meningitis, or, in rare cases, noninfectious inflammatory etiologies.

Flow cytometry and DNA single-cell cytometry are two techniques that measure the chromosomal content of cells. Flow cytometry is two to three times more sensitive than cytology for the detection of hematologic malignant cells in the CSF. ^, In leukemic or lymphomatous meningitis (e.g., LMD in patients with hematologic malignancies), nonspecific markers of LMD include elevation of β-glucoronidase, β-microglobulin, and isoenzyme V of lactate dehydogenase. Epithelial cell adhesion molecule (EpCAM) is expressed by solid tumors of epithelial origin like non–small-cell lung cancer, breast cancer, or ovarium cancer. EpCAM-based flow cytometry assay is superior to CSF cytology for the diagnosis of LMD in patients with epithelial tumors.

Case. A 51-year-old female was diagnosed with left breast invasive lobular carcinoma, tumor >5 cm, involvement of one to three axillary lymph nodes, and no distant metastases (pT3N1M0), grade 2, estrogen receptor 100%, progesterone receptor 10%, HER2 negative. She underwent bilateral mastectomies followed by two lines of chemotherapy and hormonal therapy including adriamycin plus cyclophosphamide, followed by taxol, tamoxifen, and anastrozole. Six years later, she developed widespread skeletal metastases involving the entire spine. Treatment was switched to fulvestrant and palbociclib followed by capecitabine and navelbine. Two years later, she presented with morning headaches, diplopia, dysarthria, difficulty swallowing, neck pain, and paresthesia in bilateral lower extremities. On examination, she had hypoesthesia and decreased strength (4/5) in bilateral lower extremities and cranial nerve XII palsy. Her Karnofsky performance status (KPS) was 80%. MRI Brain and Spine revealed enhancement along the cerebral sulci, cerebellar folia, and brainstem as well as spinal cord ( Fig. 15.1 ). She received systemic treatment with exemestane and underwent Ommaya placement. CSF from Ommaya was positive for malignancy. She underwent whole brain radiation treatment (WBRT) and subsequently received intrathecal chemotherapy with topotecan. CSF cleared after two doses of topotecan. Treatment was complicated by chemical meningitis after cycle three and bacterial meningitis after cycle four. Intrathecal treatment was discontinued. She had progression of her systemic disease, gallstone pancreatitis, and significant deterioration in performance status. She was transitioned to hospice care 3 months post-diagnosis of LMD and succumbed to disease 5 months after her LMD diagnosis.

(A) MRI of the cervical spine: T1-weighted gadolinium enhanced sagittal view with abnormal linear enhancement of leptomeninges along the anterior and posterior aspects of the cervical and thoracic spine. (B) MRI of the brain: T1-weighted gadolinium enhanced axial view with abnormal enhancement along the cerebral sulci and cerebellar folia and brain stem.

Teaching Points: MRI plays an important role in diagnosing leptomeningeal disease and evaluating for extent of bulky, nodular disease that guides therapy decisions. This case highlights the role of the clinical examination and imaging in diagnosing LMD in patients with cancer and the multimodality therapeutic options available for treating LMD. Positive radiologic findings in a patient with supportive clinical signs and symptoms are suggestive of CSF involvement in patients with known malignancy. In this case, there was high suspicion for LMD based on the clinical presentation. This was confirmed by MRI Brain, which showed findings consistent with a diagnosis of LMD. Due to the clinical and unequivocal radiographic evidence of LMD, CSF analysis was deferred, as the outcome was not going to impact management. That is, regardless of whether CSF cytology was negative or positive for malignant cells, the patient was planned for treatment as presumed LMD.

Utility of imaging for diagnosing LMD. MRI Brain and Spine with and without contrast is not the gold standard for diagnosis of LMD. MRI can be negative in patients with active leptomeningeal malignancy. However, MRI helps identify location, evaluate for bulky or nodular disease (>2 mm in thickness) that may not respond well to intrathecal therapy, and helps guide treatment. ^, If cranial nerve involvement is suspected, thin cuts through the brainstem should also be performed. The most frequent MRI findings include focal or diffuse enhancement of leptomeninges along the sulci, cranial nerves and spinal nerve roots, linear or nodular enhancement of the cord, and thickening of lumbosacral roots. If MRI Brain is contraindicated, then CT Brain and Spine with and without contrast can be performed.

CSF flow study . For patients who may undergo intrathecal chemotherapy, the patency of CSF pathways and normal CSF flow is imperative to ensure adequate circulation of intra-CSF chemotherapy. A radionuclide cisternogram is a nuclear medicine test that evaluates CSF flow and determines the patency of the ventricular and cerebrospinal pathways. This study involves dural puncture and injection into the CSF of the radionuclide tracer DPTA tagged with Indium-111. Repeat imaging is performed at 48–72 hours. Abnormal CSF flow interferes with uniform distribution of intrathecal chemotherapy and can lead to excess build-up of chemotherapy causing toxicity and limiting therapeutic efficacy. In these clinical cases, intrathecal therapy would not be advised. In patients, particularly those with bulky or nodular meningeal disease, CSF flow may be disrupted. In these patients, radiation therapy may have the ability to restore CSF outflow, which helps facilitate administration of intrathecal chemotherapy.

Approach to managing patients with LMD

This case also highlights the approach to managing patients with LMD. Treatment of these patients is complex and is best guided by a multidisciplinary team. Radiation (focal or WBRT), intrathecal chemotherapy, and systemic treatments may all be utilized for cancer-directed therapy. In patients for whom treatment is contraindicated due to poor performance status, supportive care is often the most reasonable option. Risk stratification can help to guide decision making, and in general, patients can be divided into high-risk or low-risk. High-risk patients are those with poor performance status (KPS <60%), progressive systemic disease with minimal or no treatment options, and bulky LMD with major neurological deficits. Low-risk patients are those with good performance status (KPS >60%), minimal or well-controlled systemic disease with favorable treatment options, and minor neurological deficits.

Factors affecting approach to treatment . Several factors influence treatment of LMD including: (1) solid versus hematologic malignancy, (2) the state of systemic cancer (stable versus progressive disease), (3) the presence of bulky versus non-bulky LMD metastasis, (4) patient performance status, and (5) clinical symptom burden. In general, the goals of treatment are to improve patient symptoms and treat the cancer ( Fig. 15.2 ).

[ED1]Goals of treatment for LMD. Both cancer-directed and palliative/symptomatic treatments may coexist in LMD management. Exclusive symptomatic treatment is opted in cases where patients cannot tolerate cancer-directed treatment. LMD , Leptomeningeal disease.

Symptomatic Treatment

For patients with high-risk disease, supportive care alone is typically preferred. Palliative and hospice care should be considered and a primary goal of managing patient symptoms should be pursued. Symptomatic treatments may involve management of elevated ICP or management of localized symptoms from infiltration at specific regions of the neuroaxis.

Management of elevated ICP . Symptoms of elevated ICP and hydrocephalus (communicating and noncommunicating) include headache, gait unsteadiness, and nausea/vomiting. These symptoms are managed by pharmacologically or mechanically lowering ICP. Communicating hydrocephalus is typically due to malignant cells in the subarachnoid space that obstruct normal CSF reabsorption pathways. Pharmacologic lowering of ICP includes administration of diamox (decreases CSF production), mannitol (osmotic agent that decreases cerebral blood volume), and corticosteroids (decreases vasogenic edema and reduces resistance to CSF outflow). Mechanical lowering of ICP is achieved by CSF diversion through placement of an external ventricular drain (temporary) or VP shunt (permanent). At times WBRT may also be considered for treating bulky meningeal disease, allowing CSF reabsorption and lowering ICP. VP shunt remains a valid option for cancer patients with low KPS, as it improves the quality of life. Although intraperitoneal seeding remains a possibility, it has not been encountered or reported in studies. ^, Noncommunicating hydrocephalus (e.g., obstructive hydrocephalus) is due to focal lesions obstructing CSF flow. Obstructive hydrocephalus is managed by removing the obstruction, either through focal radiotherapy (RT) to an obstructing lesion or, in rare cases, surgical intervention. Corticosteroids can be temporarily used for treating elevated ICP. Dexamethasone is the corticosteroid of choice and is frequently administered at doses of 16 mg/day and tapered over 1–2 weeks until definitive treatment is performed. ^,

Seizure management . Patients with LMD who do not have a history of seizures do not require empiric seizure prophylaxis. If seizures do occur, patients are treated with antiepileptic drugs that are similar to those used for primary brain tumors, metastatic brain tumors, and other lesional epilepsies. Clinicians may consider agents such as levetiracetam, lacosamide, zonisamide, topiramate, or other agents. In general, agents that are known to strongly induce or inhibit cytochrome P450 (CYP) enzymes, including carbamazepine, phenytoin, and phenobarbital, are avoided, as these can interact with chemotherapies used to treat systemic disease.

Other symptomatic managements . Patients may also suffer from symptoms due to cranial neuropathy, cauda equina involvement, and other sites of disease. When present, paresthesias and neuropathic pain may be treated with gabapentin, pregabalin, duloxetine, or amitriptyline. New-onset radicular pain in a cancer patient should raise strong suspicion for LMD and responds well to corticosteroids and/or focal radiation. Radiation to focal lesions along the neuro-axis may alleviate various symptoms including radicular pain, extremity weakness, cranial nerve deficits, urinary incontinence, and constipation. Patients with cranial neuropathies may require supportive measures due to involvement of oculomotor cranial nerves III, IV, VI, and cranial nerve VII. This may include an eye patch for diplopia, and eye drops or corneal lubrication for patients with peripheral facial nerve palsy who are unable to completely close their eye. Other interventions include implementing scheduled voiding or catheterization for urinary incontinence. Antidepressants may be beneficial for patients suffering from depression. Neurologic stimulants may be considered for patients with cancer- and/or treatment-associated fatigue (i.e., modafinil, methylphenidate).

Cancer-directed treatment

For patients with reasonable performance status, aggressive treatments aimed at decreasing the number of circulating cancer cells in the CSF and decreasing the burden of disease are considered. Historically, radiation therapy was the mainstay to treatment, but systemic and intrathecal therapies are also utilized. Treatment must be individualized based on patient- and tumor-specific factors to achieve the best results.

Clinical Pearls

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  The most frequent MRI findings of LMD are focal or diffuse enhancement of leptomeninges along the sulci, cranial nerves and spinal nerve roots, linear or nodular enhancement of the cord, and thickening of lumbosacral roots.

  
  
• 2.
  

  Neuroimaging also helps define the extent of disease and the presence of bulky/nodular disease that may require radiation or selected high-dose systemic therapies.

  
  
• 3.
  

  Cancer-directed treatment is individualized based on various factors including the type of malignancy (e.g., solid versus hematologic malignancy), performance status, type and state of systemic cancer, burden of leptomeningeal disease, and clinical symptoms.

  
  
• 4.
  

  Symptomatic treatments include management of elevated intracranial pressure, seizure treatment, supportive care for cranial neuropathies, and pain control.