I. What every physician needs to know.

Primary central nervous system lymphoma (PCNSL) is defined by the World Health Organization classification system as an extranodal malignant lymphoma arising in the central nervous system (CNS) in the absence of lymphoma outside the nervous system at the time of diagnosis.

II. Diagnostic Confirmation: Are you sure your patient has central nervous system lymphoma

The diagnosis is confirmed pathologically, either by cerebrospinal fluid (CSF) cytology, CSF flow cytometry or by stereotactic biopsy of the lesion.

A. History Part I: Pattern Recognition:

The presentation will depend on the area of the CNS that is involved with tumor. The most common presenting symptom is progressive focal neurologic deficit, which is seen in 70% of patients. Forty three percent present with neuropsychiatric symptoms, 33% with signs of increased intracranial pressure, 14% with seizures, and 4% with ocular symptoms.

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B. History Part 2: Prevalence:

The highest incidence of the disease is in the population older than 60 years of age with a rate of 16 per one million person years. This has been relatively steady since 1994. There was an increase in the rate of the disease in the 20-59 year old population, which started in the mid 1980’s, peaking in 1995.

There has been a decline in the incidence in this population since then. This is presumed to be due to the acquired immune deficiency syndrome (AIDS) epidemic, as one of the greatest risk factors for contracting the disease is immunodeficiency. This can be through human immunodeficiency virus (HIV) infection, congenital immune deficiency or immune suppression with medications.

Epstein-Barr virus (EBV) infection is associated with HIV-associated PCNSL; this association does not exist in the immunocompetent patient. There is also an association between PCNSL and autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The male to female ratio is 1.2:1 and 7.38:1 in immunocompetent and AIDS-associated PCNSL respectively.

C. History Part 3: Competing diagnoses that can mimic central nervous system lymphoma.

  • Malignant lesions: other primary CNS malignancies, other malignancies metastatic to the CNS.

  • Benign lesions: subacute infarction, multiple sclerosis, granulomatous diseases; infectious lesions: toxoplasmosis, syphilis.

D. Physical Examination Findings.

The physical exam findings are variable depending on the location of the lesion, but they tend to be neurologic in nature. One important measurement is to follow the cognitive functioning of the patient, since one of the most significant morbidities is a decline in cognitive function. This is particularly true for those greater than 60 years of age. The recommended modality is to follow serial mini-mental status exams to document the patient’s cognitive ability.

E. What diagnostic tests should be performed?

Slit lamp exam should be used, as ocular seeding is seen in 20% of patients. Color photography of the posterior pole of the eye should be performed if the eye exam is positive for malignancy.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

  • Complete blood count (CBC), basic metabolic panel (BMP), liver function tests (LFTs), lactate dehydrogenase (LDH), and serologic testing for HIV.

  • Lumbar puncture unless contraindicated as CSF dissemination is seen in 15-40% of patients.

  • Bone marrow biopsy to evaluate for systemic disease.

  • Fertility preservation such as sperm banking for men.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

  • Magnetic resonance image (MRI) of the cerebrospinal axis.

  • Computed tomography (CT) scan of the chest abdomen and pelvis to evaluate for systemic disease.

  • Testicular ultrasound as testicular lymphoma is associated with CNS involvement.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Positron emission tomography (PET) scan may be used in the future, but currently the data do not support its widespread usage for staging of this disease.

III. Default Management.

The first step in management is to secure the diagnosis. This should be done either through CSF evaluation or through stereotactic biopsy of the lesion. Hematology and Medical Oncology consultants should be involved.

Primary therapy is with a high-dose methotrexate-containing regimen utilizing leucovorin rescue. The management includes preparing the patient to receive high-dose methotrexate with adequate hydration, with half-normal saline with sodium bicarbonate. The goal is to have a urine output of greater than 100 ml/hour and a urine pH greater than 7 for 4 consecutive hours.

The preferred surgical procedure is stereotactic biopsy of the lesion. Surgical resection has not been shown to improve survival.

A. Immediate management.

If the patient is having significant symptoms then corticosteroids can be administered. However, due to the tumor lysis that occurs with corticosteroid administration, they should be withheld, if possible, until after the biopsy is performed as they may result in false negative results.

B. Physical Examination Tips to Guide Management.

Oral examination should be carried out to evaluate for methotrexate-associated mucositis. This typically occurs 3-7 days after administration. Perform a neurologic exam to follow improvement or worsening of neurologic deficits.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Methotrexate levels should be obtained at 24 hours after initiation of therapy and every 24 hours subsequently until the level is less than 0.1 micromol/L.

D. Long-term management.

Patients are followed with serial imaging and neurologic exams to monitor for response to therapy or for disease progression.

E. Common Pitfalls and Side-Effects of Management

Corticosteroid administration prior to biopsy may lead to false negative results. Leucovorin should be started 24 hours after the methotrexate completes.

IV. Management with Co-Morbidities

If the patient has significant comorbidities that affect the overall performance status and they are not directly related to the malignancy then alternate therapies may be considered including whole brain radiotherapy, corticosteroids, and/or hospice placement.

A. Renal Insufficiency.

Methotrexate is to be used with caution in patients with abnormal renal function and the dose should be adjusted in proportion to the creatinine clearance.

B. Liver Insufficiency.

Methotrexate can cause elevation in the transaminases and bilirubin, particularly with high dose therapy. This usually occurs within the first day of therapy and returns to normal by day 10. Methotrexate half-life is prolonged in patients with third space fluid collections such as ascites, leading to increased toxicity.

C. Systolic and Diastolic Heart Failure

Methotrexate half-life is prolonged in patients with third space fluid collections, leading to increased toxicity.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management. Aspirin inhibits the renal excretion of methotrexate.

E. Diabetes or other Endocrine issues

Corticosteroid administration may exacerbate diabetes.

F. Malignancy

Patients with bladder cancer status post-cystectomy with ileal conduit diversion are at increased risk for delayed elimination of methotrexate.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management. Omeprazole increases methotrexate levels.

J. Hematologic or Coagulation Issues

One of methotrexate’s dose-limiting toxicities is myelosuppression. Leukocyte nadir at day 4-7 with recovery by day 14.

Methotrexate may enhance the anticoagulant effect of warfarin.

K. Dementia or Psychiatric Illness/Treatment

Whole brain radiotherapy should not be used as a treatment option if there is baseline neurocognitive decline.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Methotrexate therapy is associated with a cerebral dysfunction consisting of paresis, aphasia, behavioral abnormalities, and seizure. This usually occurs within 6 days of therapy and resolves in 48-72 hours.

B. Anticipated Length of Stay.

The high dose methotrexate therapy is given as an inpatient. The patient is hospitalized until the methotrexate level is less than 0.1mol/L.

C. When is the Patient Ready for Discharge.

The patient is hospitalized until the methotrexate level is less than 0.1mol/L.

D. Arranging for Clinic Follow-up


1. When should clinic follow up be arranged and with whom.

Follow-up should include Hematology, Medical Oncology and Radiation Oncology. In the event of ocular involvement, follow-up with Ophthalmology should be included. Patients are typically scheduled into the oncology clinic within 1-2 weeks of discharge as the regimen is typically administered every 28 days.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Complete metabolic profile (CMP), CBC.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

MRIs are the best imaging modality to follow the disease and they should be performed every 2 months while on therapy. They should be performed sooner if there are any new neurologic symptoms.

E. Placement Considerations.

In the event that the patient is unable to tolerate therapy, hospice placement would be appropriate. If the neurologic deficit is such that the patient is unable to complete their activities of daily living, then a nursing home or skilled nursing facility would be appropriate.

F. Prognosis and Patient Counseling.

A retrospective analysis revealed five negative prognosticators: age greater than 60, ECOG PS (Eastern Cooperative Oncology Group performance status) greater than 1, elevated LDH, high CSF protein, and involvement of the deep regions of the brain.

Chemotherapy alone with a methotrexate-containing regimen has a median survival of 50 months. Almost all patients with PCNSL will experience relapse or progression and will require salvage therapy.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.


B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

This disease is treated with an inpatient chemotherapy regimen that will frequently require readmission every 28 days.

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