Case. A 71-year-old male presented with altered mental status. He had a history of B-cell NHL diagnosed 5 months prior to presentation. He initially presented with abdominal and back pain and was found to have a mesenteric and paraspinal mass extending from T6 to T10, with spinal and epidural involvement. Biopsy of the mesenteric mass was consistent with high-grade, CD10+ B-cell lymphoma with MYC and BCL-2 rearrangements (double-hit). Bone marrow biopsy and CSF were negative for disease. He received radiation treatment for the paraspinal mass and chemotherapy with rituximab plus bendamustine for three cycles, the last cycle being completed 1 month prior to current presentation. Recent PET scan had shown partial response with residual mesenteric and paraspinal masses.

The patient then developed visual disturbances and incoordination 6 weeks prior to current presentation. He was eventually found in his car confused with incoherent speech. On examination, he was lethargic with eyelid opening apraxia, dysarthria, and increased tone in bilateral upper extremities and right lower extremity.

The differential diagnosis for suspected subacute encephalopathy included toxic, metabolic, infectious, inflammatory, and neoplastic conditions, which are summarized in Table 23.1 .

Brain MRI showed increased T2 signal in the dorsal midbrain, medial thalami, hypothalamus, optic tracts, anterior fornix, and periventricular white matter. There was aqueductal effacement and enlargement of the lateral ventricles suggestive of obstructive hydrocephalus ( Fig. 23.1A ). Post-gadolinium images showed abnormal enhancement of the leptomeninges and septum pellucidum ( Fig. 23.1B ). Electroencephalogram (EEG) showed generalized slowing. CSF analysis revealed elevated protein (57 mg/dL) with normal white blood cell (WBC) count and glucose level. Cytology was negative. Flow cytometry was not performed due to paucity of cells present in the CSF. Due to finding of hydrocephalus, ventriculoperitoneal shunt was placed and the patient experienced significant improvement of mental status. Flow cytometry of ventricular fluid showed an atypical B-cell population, positive for CD19, CD20, and CD10. Diagnosis of leptomeningeal recurrence of NHL was made and treatment with high-dose intravenous (IV) methotrexate and rituximab was initiated.

(A) Axial MRI fluid-attenuated inversion recovery images showing increased T2 signal intensity in the dorsal midbrain, medial thalami, hypothalamus, optic tracts, anterior fornix, and periventricular white matter. Enlargement of the lateral ventricles is suggestive of obstructive hydrocephalus. (B) Axial T1 post-gadolinium MRI showing abnormal enhancement of the leptomeninges and septum pellucidum.

Teaching Points: Diagnosis and Management of Lymphomatous Meningitis. Leptomeningeal involvement by NHL results from the multifocal seeding of the leptomeninges by cancer cells (also see Chapter 15 , Case 15.2). Many patients have concurrent leptomeningeal and parenchymal involvement. Leptomeningeal disease may be seen in 4–15% of patients with NHL. It is very rare in patients with HL.

The clinical presentation of leptomeningeal involvement is typically characterized by multifocal neurological signs including cranial neuropathies (diplopia, facial weakness, hearing loss, imbalance, vertigo, dysphagia, hoarseness), extremity weakness or sensory changes, occasionally spinal cord symptoms (incontinence), headache, and communicating hydrocephalus. Testing should include MRI of the entire neuroaxis and CSF analysis including cytology and flow cytometry. In hematologic malignancies, flow cytometry is significantly more sensitive in detecting abnormal cells in CSF than conventional cytology and should be routinely used when lymphomatous involvement is suspected. Consideration should be given for radionuclide CSF flow study to evaluate for obstruction if bulky disease or hydrocephalus occurs, as impaired CSF flow is a relative contraindication for intrathecal (IT) chemotherapy.

MRI demonstrates focal or diffuse leptomeningeal contrast enhancement, subarachnoid nodules, or intradural root enlargement with enhancement. CSF may reveal lymphocytosis, increased protein, and low glucose. A unique CSF feature in leptomeningeal HL is eosinophilic pleocytosis, and identification of Reed-Sternberg cells in the CSF gives the definitive diagnosis.

First-line treatment of NHL leptomeningeal metastases is typically high-dose intravenous (IV) methotrexate. Other com monly used drugs are cytarabine and thiotepa. If no CSF flow obstruction is detected, IT chemotherapy can also be considered. Clinical trials of new IT agents such as rituximab are underway. Focal radiotherapy might be needed to treat bulky disease obstructing CSF pathways, but because of its significant toxicity, it is rarely used.

For NHL patients with leptomeningeal metastases, prolonged overall survival was associated with being near the median age, with an early diagnosis, a low International Prognosis Index score, higher Karnofsky Performance Scores, and concurrent parenchymal involvement.

In leukemia, leptomeningeal involvement is most common in ALL. It is identified in less than 10% of adults at diagnosis, but occurs in 30% to 50% of patients at leukemic relapse. Due to the high incidence of CNS involvement, CNS prophylaxis is recommended in all patients with ALL.

Case. A 64-year-old female presented with a breast mass and axillary lymphadenopathy. Biopsy of the breast mass demonstrated DLBCL, whereas the axillary lymph node biopsy revealed small lymphocytic lymphoma with evidence of clonal B-cells. It was unclear if the two cancers were clonally related. She had no neurological symptoms at the time of diagnosis and brain MRI was normal. She underwent six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), as well as two doses of IT methotrexate (e.g., CNS prophylaxis for high-risk disease). Following R-CHOP, she received consolidative radiation to her breast and had no evidence of recurrent lymphoma for 2 years. She then presented with confusion and brain MRI showed an enhancing mass in the splenium of the corpus callosum that was hypermetabolic on CT-PET. CSF flow cytometry revealed a clonal B-cell population, and the diagnosis of secondary CNS lymphoma was made. She underwent treatment with nine cycles of methotrexate, rituximab, and temozolomide (MRT) followed by consolidation with etoposide and cytarabine, with resolution of her brain lesion. One year later, her family noted progressive cognitive difficulties, and a repeat brain MRI showed new enhancing lesions in the left cerebellum, brainstem, and left basal ganglia ( Fig. 23.2 ). CSF analysis revealed a small lambda monotypic B-cell population confirming CNS relapse. She was reinitiated on MRT for six cycles with resolution of the brain lesions, and then placed on monthly maintenance high-dose IV methotrexate for 12 months, in addition to 6 months of maintenance temozolomide.

Axial T1 post-gadolinium brain MRI from the patient’s second central nervous system (CNS) recurrence, pre- and posttreatment. (A) CNS relapse with enhancing lesions of the left cerebellum, brainstem, and left basal ganglia. (B) Images obtained 6 months after treatment initiation showing resolution of the enhancing lesions.

Teaching Points: CNS Recurrence May Occur in High-Risk Systemic Lymphoma. Routine CNS prophylaxis in DLBCL is only recommended in patients with high-risk of CNS involvement. Initial involvement of the breast indicates a more aggressive form, with a 9–27% risk of developing secondary CNS lymphoma. This patient was therefore considered high-risk and treated with two doses of IT methotrexate. National Comprehensive Cancer Network (NCCN) guidelines currently recommend four to eight doses of IT chemotherapy, although treatment practices vary greatly due to lack of clear evidence. CNS recurrence often presents in isolation soon after diagnosis or after completion of chemotherapy (4.7–9 months). Parenchymal metastases occur in 1% to 2% of NHL and in 0.2% to 5% of HL. Compared with other lymphomas, DLBCL is more likely to manifest with a parenchymal lesion than leptomeningeal disease. Common clinical presentations of a new parenchymal mass include new-onset headaches, focal deficits, and changes in mental status, coma, or seizures. Workup of suspected CNS relapse should include MRI of the brain with and without contrast, CSF cytology and flow cytometry, and evaluation for systemic recurrence. Parenchymal lesions on brain MRI are typically multiple, homogeneously enhancing, and periventricular, sometimes accompanied by leptomeningeal or subependymal enhancement. Treatment of secondary CNS lymphoma includes systemic high-dose methotrexate and rituximab, frequently R-CHOP, with recent evidence supporting the use of temozolomide. Newer agents are currently being explored, such as ibrutinib and lenalidomide. Surgery is reserved for lesions causing mass effect and treatment with radiation has failed to show improvement in survival.