Cancer complications in patients with hematologic malignancies

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.

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.