AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Primary central nervous system lymphoma (PCNSL) has been known by many other names, including reticulum cell sarcoma, diffuse histiocytic lymphoma, and microglioma. The proliferation of names reflects initial uncertainty about the cell of origin. PCNSL is now known to be a rare form of extranodal high-grade non-Hodgkin B-cell neoplasm, usually large cell or immunoblastic type. It originates in the brain, leptomeninges, spinal cord, or eyes, typically remains confined to the CNS, and rarely spreads outside the nervous system. Therefore, it can be classified as stage 2 disease.

Previously, a rare tumor accounting for less than 2% of cerebral neoplasms, PCNSL is being seen with increasing frequency in immunocompetent patients, patients with AIDS, and transplant recipients, accounted for 2.7% of all primary brain tumors diagnosed in the United States from 1995-1999 (CBTRUS 2002-2003). Although the cells of origin are B lymphocytes, PCNSL should be considered a brain tumor because its therapeutic challenges resemble those of other brain tumors. In particular, drug delivery is impaired by the blood-brain barrier, and cerebral toxicity limits the use of available treatment modalities. Most PCNSLs (about 90%) are diffuse large B-cell lymphoma (DLBCL); the remaining 10% are poorly characterized low-grade lymphomas, Burkitt lymphomas, and T-cell lymphomas (Miller, 1994).

Pathophysiology

PCNSL arises from B lymphocytes, which are usually small, noncleaved, or immunoblastic cells. The DLBCL type of PCNSL is composed of immunoblasts or centroblasts that have a predilection for blood vessels. Lymphoid clustering around small cerebral vessels is typically seen. Reactive T-cell infiltrates can also be present in varying degrees.

In a recent study involving 32 PCNSL cases for expression of proteins found at different stages in lymphocyte development (Sugita, 2004), tumor specimens were immunophenotyped for antigens associated with germinal centers (CD10, Bcl-6) and with nongerminal center stages (SHP-1, CD138). In 30 of 32 cases, tumors were positive for SHP-1 but negative for CD138, supporting the concept that PCNSLs originate from a later germinal center to an early postgerminal center, and they may be capable of further maturation steps. However, current evidence argues against the possibility that malignant lymphocytes perform further maturational steps (Montosenos-Rongen, 2005). The tumor likely arises in an extraneural environment with subsequent localization to the CNS, possibly by virtue of a specific neurotropism.

Also, it has been reported (Linnebank, 2004) that overexpression of BCL-6 was associated with improved survival (median, 101 months) compared with those tumors that did not express BCL-6 (median, 14.7 months). Further search is on for the identification of additional markers prognosis.

Its predilection for certain cerebral sites gives rise to the characteristic appearance on neuroimaging studies. Seventy-five percent of immunocompetent patients with these tumors have solitary lesions. The dense cellularity of the tumor accounts for its isodense or hyperdense appearance on nonenhanced CT scan and hypointense appearance on long TR-weighted MRI.

Following administration of either iodinated contrast for CT or gadolinium for MRI, almost all PCNSLs enhance homogeneously (see Imaging Studies). PCNSLs are assumed to be diffusely infiltrative at the time of presentation. The areas of disease are not visible on neuroimaging studies because they are behind a relatively intact blood-brain barrier. Primary symptoms may result from local mass effect due to raised intracranial pressure, from ocular involvement, or from focal deposits on cranial or spinal nerve roots.

Frequency

United States

PCNSL incidence has risen steadily over the past 10-15 years. Incidence in immunocompetent patients is approximately 51 per 10,000,000 per year.

PCNSL has been reported in 6-20% of HIV-infected patients, and the incidence is expected to rise as patients with low CD4+ counts survive longer.

International

Similar trends toward rising frequency of diagnosis of PCNSL are reported.

Mortality/Morbidity

• Whole-brain radiation therapy had been the primary treatment for PCNSL for the past 10 years. Initial clinical and radiographic improvement rates were high, but the duration of response was short and median survival duration averaged only 10-18 months.
• With radiation therapy alone, patients with AIDS have a median survival duration of only 4 months.
• Chemotherapy has extended median survival duration in immunocompetent patients to 44 months. A subgroup of patients with AIDS who are able to tolerate chemotherapy and radiation therapy may have a median survival duration as long as 18 months.

Sex

• Among immunocompetent patients with PCNSL, males outnumber females by approximately 2:1.
• Almost 95% of HIV-infected patients with PCNSL are males.

Age

• Median age of immunocompetent patients with PCNSL is 55 years.
• Median age of HIV-infected patients with PCNSL is 35 years. The overwhelmingly common risk factor for HIV-related PCNSL is intravenous drug abuse.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The most typical presentation of PCNSL in an immunocompetent patient is progressive focal symptoms indicative of a mass lesion. Seizures may occur. Sometimes, nonspecific mental status change leads to the diagnosis. Several variant presentations of PCNSL are discussed in this section.

• Patients with AIDS are more likely to present with an encephalopathy than other patients with PCNSL. This correlates with the more often multifocal, diffuse enhancement pattern seen on MRI. A history of concurrent infections is quite common, and the median CD4+ count is 20/mm³. Much of the history taking should be devoted to establishing whether the patient may have immune deficiency. A careful sexual and drug abuse history is necessary. If the patient is a transplant recipient, the nature and duration of immune suppression must be clarified.
• Diagnosis of PCNSL in both immunocompetent and immunocompromised patients is particularly difficult if they present with one of the variant syndromes outlined here.
• • Isolated, ocular, or meningeal tumor may occur in the absence of any focal abnormalities on MRI. Such patients give a history of (1) blurred vision, (2) headache, (3) isolated cranial nerve dysfunction (eg, diplopia, dizziness, dysphagia, facial numbness, monocular visual loss), or (4) spinal nerve root symptoms (eg, pain, dysfunction localized to one dermatome, bowel or bladder problems).
  • Relapsing, remitting lesions may disappear for periods as long as several months to a year or more. Administration of corticosteroids may cause prolonged remission of clinical and radiographic signs and symptoms, but remission also occurs spontaneously.
  • Progressive dementia or stupor with no focal signs and with little or no enhancement on MRI may be more common in patients with AIDS who have PCNSL.
  • Intravascular malignant lymphomatosis (previously called neoplastic angioendotheliosis) is a series of strokelike focal events, and the MRI may look like multiple large- and small-vessel strokes. Cerebral vessels are filled with neoplastic B lymphocytes.
  • Neurolymphomatosis is the only PCNSL syndrome that involves both the central and peripheral nervous systems at presentation. Cerebral lymphoma with focal mass lesions as well as infiltration of peripheral nerves are seen.

Physical

• The goal of the general physical examination is to detect possible extraneural sources of lymphoma.
• • Lymphadenopathy
  • Abdominal masses
  • Skin lesions (sarcoidosis may mimic PCNSL on neuroimaging studies, or cutaneous lymphoma may be present)
• Neurologic examination should be directed to determining which compartments of the nervous system are involved.
• • Eye examination for vitreous involvement: This will require ophthalmologic consultation and slit-lamp examination and is a necessary part of the workup in all patients with PCNSL who have raised intracranial pressure. Papilledema may be present.
  • Examination for focal deficits
  • Examination of peripheral nerves for evidence of neuropathy (suggestive of systemic process or neurolymphomatosis)

Causes

• Immunocompetent patients
• • No clear risk factors for PCNSL in immunocompetent patients are known.
  • The disease is more common among men (male-to-female ratio is 2:1) and in the elderly.
  • Corboy et al have reported that 56% of a group of both immunocompetent and immunocompromised patients had human herpes virus 8 (HHV-8) in their tumors. This is the same herpes virus that is associated with Kaposi sarcoma and with primary effusion (ie, body-cavity-based lymphomas); however, a direct causal relationship of this herpes virus to any PCNSL has not yet been established.
• Immunocompromised patients
• • Nature, intensity, and duration of immune suppression are factors in determining the risk of developing PCNSL.
  • Prolonged glucocorticoid use usually is required (>6 months).
  • Patients with AIDS generally have CD4+ counts less than 30/mm³.
  • Virtually all PCNSLs in patients with AIDS express an Epstein-Barr virus-related genome.
• Other diagnostic considerations
• • Differential diagnosis of a patient with suspected PCNSL depends on the patient's immune status and radiographic appearance of the lesions. For example, the major differential diagnostic possibilities raised in an immunocompetent patient with a solitary lesion (besides PCNSL) are high-grade primary brain tumor, such as glioblastoma, and isolated metastasis.
  • In patients with AIDS, multifocal, ring-enhancing lesions raise the question of toxoplasmosis or other opportunistic infection. More diffuse cognitive and MRI abnormalities suggest the possibility of some infectious encephalitic process such as herpes zoster, cytomegalovirus encephalitis, cryptococcal meningitis, or AIDS/dementia complex.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Abducens nerve (cranial nerve VI) palsy
Neurological infections
Granulomatous angiitis of the CNS

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The following should be ordered in an immunocompetent patient whose CT/MRI scan suggests PCNSL:
• • Withhold corticosteroids as their use may complicate diagnosis
  • Chest x-ray to rule out metastatic disease
  • CBC
  • HIV testing
  • Slit-lamp examination for vitreous lymphoma
  • Lumbar puncture for cells, glucose, protein, and cytology in the cerebrospinal fluid (CSF)
• The following should be ordered in an HIV-infected or other immunocompromised patient whose CT/MRI scan suggests PCNL:
• • Avoid corticosteroids
  • Chest x-ray
  • Toxoplasma gondii serology
  • Slit-lamp examination for vitreous lymphoma
  • Lumbar puncture for cells, glucose, protein, cytology, syphilis testing, and cryptococcal antigen

Imaging Studies

• MRI of the brain shows a hypointense lesion or lesions on long TR-weighted images, which enhance densely and homogeneously after contrast administration. Lesions are multifocal in 50% of patients with AIDS, whereas only 25% of immunocompetent patients have multifocal disease at presentation. MRI also gives information about leptomeningeal enhancement, hydrocephalus, and concurrent alternative diagnoses, such as infections in patients with AIDS.
• MRI of the spine with contrast should be performed in patients with focal, spinal, or root symptoms, as they may require radiation to localize the deposits of lymphoma.
• Thallium 201 single-photon emission computed tomography (SPECT) scanning is appropriate in patients with AIDS to help distinguish between infectious processes and PCNSL. Patients with AIDS may have a cystic, ring-enhancing lesion with PCNSL instead of the homogeneously enhancing abnormalities seen in immunocompetent patients. The presence of single or multiple ring-enhancing lesions in patients with AIDS raises suspicion of toxoplasmosis, Nocardia asteroides infection, or neurosyphilis.
• Chest and abdominal CT scans should be performed because a small minority of immunocompetent patients (only a dozen or so reported in the literature so far) have an extraneural source for their cerebral lymphoma. Common sites are abdomen and breast. Therefore, after the establishment of a definitive diagnosis of PCNSL, these staging procedures should be performed. Staging of extent of extraneural lymphoma has a higher yield in patients with AIDS.

Other Tests

• Liver function tests: As the mainstay of treatment for many patients is high-dose methotrexate, hepatic function must be evaluated. Tests should include serum bilirubin (total/direct), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase.
• Twenty-four-hour urine collection for creatinine clearance: Patients being considered for methotrexate chemotherapy must have a glomerular filtration rate (GFR) of greater than 100 mL/min because inadequate renal clearance enhances methotrexate toxicity.

Procedures

• Slit-lamp examination and possible vitrectomy: Although fewer than 10% have vitreous involvement at initial presentation, all patients should undergo slit-lamp examination. Vitrectomy may establish the diagnosis, sparing brain biopsy in these patients.
• Stereotactic brain biopsy: Since the disease is diffusely infiltrative, craniotomy and debulking of lesions have no role in PCNSL. Open brain biopsy may be necessary in those patients who have lesions located in areas of the brain that are difficult to access (eg, brain stem). If possible, the procedure should be performed before corticosteroids have been administered.

Histologic Findings

PCNSL is a densely cellular, aggressive non-Hodgkin B-cell lymphoma. Immunocompetent patients usually have a small, noncleaved cell or immunoblastic subtype. Perivascular clusters of lymphocytes and T-lymphocyte infiltrates are common in immunocompetent patients. T-lymphocyte infiltrates are not found in patients with AIDS.

HHV-8, also known as Kaposi sarcoma-associated herpes virus, has been documented in 56% of a group of immunocompetent and AIDS patients with PCNSL. Virtually all PCNSLs in patients with AIDS express a Epstein-Barr virus-related genome.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The goal of treatment is eradication of both contrast-enhancing mass lesions and microscopic infiltration of brain, spine, leptomeninges, and vitreous. Successful therapy in immunocompetent patients leads to a median survival duration as long as 44 months. Treatment must be designed to maximize efficacy and minimize toxicity to cerebral white matter.

• The optimal treatment for PCNSL has not been established. The following recommendations are based on an ongoing protocol at the author's and several other institutions, and observation that radiation therapy alone, while initially effective, produces a median survival duration of only 18 months. Combination chemotherapy and radiation therapy more than doubled survival time but such success was achieved at the price of a greater than 50% incidence of dementia in those who survived more than 18 months on these regimens.
• The decision to offer chemotherapy as the sole initial treatment modality, therefore, must be made keeping in mind that optimal dose and timing are still under investigation. Current active protocols for the treatment of PCNSL have been described by Hoang-Xuan and Delattre.
• • Methotrexate: Methotrexate-based chemotherapy regimens have been the most successful treatment strategies to date. Methotrexate is a folate analogue which interferes with DNA synthesis and repair. For treatment of PCNSL, patients receive high-dose systemic methotrexate. Close monitoring and adjustment of intravenous fluids and calcium leucovorin rescue necessitates inpatient administration of this drug.
  • Corticosteroids: They are avoided during the initial workup, as their administration may have a direct antitumor effect on B-cell lymphoma and cause dramatic reduction in the MRI abnormalities, making biopsy and histologic confirmation more difficult. Similarly, corticosteroids should be avoided, if possible, during chemotherapy, as repair of the blood-brain barrier may decrease the delivery of methotrexate into the brain parenchyma.
  • Antiepileptic drugs: Prophylactic use of antiepileptic drugs (AEDs) should be avoided and their use should be confined to patients who experience seizures. Any of the first-line AEDs (eg, phenytoin, carbamazepine, valproic acid) would be appropriate for patients with PCNSL, although leukopenia and liver function abnormalities from any of these drugs potentially could be confused with chemotherapy-related toxic effects.

Surgical Care

• Stereotactic brain biopsy is the most appropriate method for diagnosis of PCNSL.
• Aggressive debulking has no role in the treatment of PCNSL lesions.
• At times, an open biopsy may be preferable to a stereotactic procedure if the lesion is located in a difficult-to-access area of the brain, such as the brain stem.
• Placement of an Ommaya reservoir sometimes is needed for repetitive instillation of intrathecal chemotherapy in patients with leptomeningeal lymphoma; however, it is not a routine procedure for patients with PCNSL of the brain parenchyma.

Consultations

• Ophthalmology consultation is required as part of the initial workup and staging of PCNSL to exclude vitreous involvement. Vitrectomy may be performed to establish diagnosis for patients with abnormal findings on slit-lamp examination.
• Medical oncology consultation is appropriate for any patient with suspected PCNSL who has an abnormal chest or abdominal CT scan; patients with abnormalities in CBC may need bone marrow biopsy. Before beginning treatment for PCNSL, systemic disease that would alter the planned chemotherapy drug regimen must be ruled out.

Diet

During chemotherapy with high-dose methotrexate, patients must be hydrated adequately. They must take sodium bicarbonate 3 g q4h during the 24 hours prior to and during the methotrexate therapy. They should avoid fruit juices that might acidify the urine. Drugs to be avoided during methotrexate therapy include salicylates, nonsteroidal anti-inflammatory drugs, and sulfonamides.

Activity

No major activity restrictions apply to patients with PCNSL. Vigorous physical activity is discouraged for 3 weeks following brain biopsy.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Methotrexate (MTX) is the single most effective chemotherapeutic agent for PCNSL. Standard systemic chemotherapy regimens such as CHOP (ie, cyclophosphamide, doxorubicin, vincristine, prednisone) are ineffective, presumably reflecting the difficulty of penetration of blood-brain barrier by chemotherapeutic drugs. Methotrexate, when administered in high doses systemically, achieves therapeutic levels in brain parenchyma and obviates intrathecal therapy as an initial treatment for PCNSL. Other drugs that have activity against PCNSL include cytarabine and (intrathecal) thiotepa.

Drug Category: Chemotherapy

Initial chemotherapy without radiation therapy results in excellent initial tumor response rates and avoids the toxicity associated with combined modality therapy (ie, radiation and chemotherapy).

Drug Name	Leucovorin (Wellcovorin)
Description	Minimizes systemic antifolate toxicity of MTX.
Adult Dose	Exactly 24 h after start of MTX infusion, leucovorin 25 mg IV/PO is administered q6h until MTX concentration in plasma is <1 X 10-7 M (usually achieved within 72 h of MTX infusion) Leucovorin dose adjusted on basis of MTX levels as follows (any dose of leucovorin >50 mg should be given IV): 24 h 100 mg/m2 q6h* > 1 X 10-5 M 48 h > 1 X 10-6 M 100 mg/m2 IV q6h* 48 h > 1 X 10-7 M 200 mg/m2 IV q6h* 72 h > 1 X 10-7 M 100 mg/m2 IV q6h* *Until plasma MTX levels <1 X 10-7 M
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; pernicious anemia or vitamin-deficient megaloblastic anemias
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	MTX levels must be monitored daily until rescue achieved; monitor daily electrolytes, BUN, creatinine, and CBC; do not administer intrathecally or intraventricularly

Drug Name	Cytarabine (Cytosar-U)
Description	Has significant activity against systemic lymphoma; half-life in CNS quite long owing to low rates of degradation; therapeutic levels in CSF achieved with high doses; maximally tolerated doses appear to be 3 g/m2, given most effectively as 12-h infusion No studies using cytarabine as single agent for PCNSL reported; however, has been used as second agent after relapse from MTX chemotherapy.
Adult Dose	3 g/m2 IV as 12-h infusion; dosing interval and total cumulative dose not established
Pediatric Dose	Not established for PCNSL
Contraindications	Documented hypersensitivity; prior cranial radiation therapy; uncontrolled seizures; preexisting cerebellar dysfunction (use of cytarabine occasionally complicated by development of potentially irreversible cerebellar toxicity)
Interactions	Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dosing intervals and total dose not established for PCNSL; should be prescribed solely by physicians experienced in care of patients with PCNSL, preferably as part of protocol that investigates cytarabine as initial agent with MTX, or as salvage agent for relapsed PCNSL

Drug Category: Antiemetics

These agents are useful in the treatment of nausea associated with chemotherapy and radiation therapy.

Drug Name	Ondansetron (Zofran)
Description	Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy and complete body radiotherapy.
Adult Dose	8 mg IV 30 min prior to chemotherapy; repeat after MTX chemotherapy q4h for 3 more doses while patient is awake
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Although cytochrome P-450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) have potential to change half-life and clearance of ondansetron, dosage adjustment not usually required
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	To be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting

Drug Name	Palonosetron (Aloxi)
Description	Selective 5-HT3 receptor antagonist with long half-life (40 h). Indicated for prevention and treatment of chemotherapy-induced nausea and vomiting. Blocks 5-HT3 receptors peripherally and centrally in chemoreceptor trigger zone.
Adult Dose	0.25 mg IV once (30 min before chemotherapy); administer over 30 sec; do not repeat dose within 7d
Pediatric Dose	<18 y: Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause headache, constipation, diarrhea, or dizziness

Drug Category: Corticosteroids

B lymphocytes have glucocorticoid receptors on their surfaces. This may account for the rapid antineoplastic effect of steroids. While rapid repair of the blood-brain barrier reduces vasogenic edema and ameliorates symptoms, the tumor may become more difficult to diagnose by biopsy. Similarly, the intact blood-brain barrier may make chemotherapy less effective. Therefore, corticosteroids should be avoided altogether during evaluation of a patient with PCNSL and also during chemotherapy, unless they are required for symptom control.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• After biopsy, some patients may require inpatient care because of neurological deficits related to the primary site of the tumor.
• The use of corticosteroids to control symptoms may be unavoidable, but administration of dexamethasone or its equivalent, in doses greater than 8 mg/day for more than 2 weeks, raises the risk of steroid myopathy. Patients with muscle weakness due to steroids may require inpatient rehabilitation.
• High-dose systemic methotrexate must be administered in the hospital.

Further Outpatient Care

• Recurrence or failure of first-line chemotherapy
• • Patients are monitored with monthly MRI scans after initiation of methotrexate chemotherapy. Those with primary leptomeningeal disease should undergo lumbar puncture with cytologic sampling of CSF at monthly intervals.
  • The management of progressive (ie, methotrexate failure) or recurrent PCNSL is not yet well established. The age and performance status of the patient must be considered. In general, greater than 25% enlargement of previous areas of gadolinium-contrast enhancement, appearance of new contrast-enhancing lesions, or appearance of malignant cells in the CSF, vitreous or, rarely, elsewhere in the body, constitutes treatment failure. Treatment options include the following:
    • Return from monthly (maintenance) to biweekly methotrexate therapy.
    • Consider IV cytarabine.
    • Radiation therapy is probably the best second-line anti-PCNSL treatment.
    • Chemotherapy failure indicates that combined therapy is necessary, accepting that the risk of neurotoxicity from radiation and chemotherapy is considerable. Until the efficacy of repeat intensive methotrexate therapy is established in relapsed disease or until other chemotherapeutic agents are tested more extensively, whole-brain radiation therapy with 4000 cGy in 20-25 daily treatments is recommended.

In/Out Patient Meds

• Although corticosteroids should be avoided during methotrexate therapy, their use may improve quality of life by minimizing symptoms due to vasogenic edema or tumor mass effect; the smallest effective dose should be prescribed.

Deterrence/Prevention

• Since the reasons for development of PCNSL in immunocompetent patients are unknown, whether deterrent or preventive maneuvers can be undertaken also is unknown.
• • Patients receiving immunosuppressive therapy after organ transplantation should receive the smallest effective doses compatible with viability of the transplant. Corticosteroid-sparing therapy is advised, and lowering intensity of immunosuppression, if feasible, is advised for transplant recipients who develop PCNSL.
  • Patients with AIDS who have low CD4+ counts are at greatest risk for PCNSL. The extent to which highly effective antiretroviral therapy will affect the incidence and prognosis of PCNSL in AIDS is not yet known.

Complications

• The major complications of methotrexate therapy are discussed in Medication.
• Long-term sequelae of radiation therapy and chemotherapy in PCNSL are significant. Although median survival duration has been extended with combined chemotherapy and radiation therapy, the percentage of survivors with late cerebral white-matter toxicity resulting in cognitive dysfunction approaches 50%.
• Serious leukoencephalopathy also is seen in patients receiving methotrexate chemotherapy alone, but the incidence appears to be lower than that of the cerebral white-matter toxicity seen with combination therapy.

Prognosis

• Immunocompetent patients
• • The initial response to radiation therapy is excellent, often resulting in complete resolution of radiographic abnormalities. Nevertheless, the duration of response is short, and median survival duration with radiation therapy alone averages only 18 months. Relapse in patients with parenchymal disease is usually within the brain, though leptomeningeal, vitreous and, rarely, systemic recurrences are reported.
  • Methotrexate-based chemotherapy as the sole treatment modality results in median survival duration approaching 48 months.
• Patients with AIDS
• • Patients with AIDS have only a 4-month median survival duration with radiation therapy. Untreated, such patients often die within 2.5 months, sometimes because of coexisting infections.
  • Extended survival in subgroups of HIV-infected patients with CD4+ counts greater than 200/mm³ and no concurrent opportunistic infections have been reported. With a regimen of intrathecal methotrexate, concurrent systemic procarbazine, cyclohexylchloroethylnitrosurea (CCNU), vincristine, and whole-brain radiotherapy, this small subset of patients with AIDS had median survival durations ranging from 10-18 months.

Patient Education

• Patients receiving high-dose intravenous methotrexate must be educated carefully about the drugs to be avoided in the week prior to chemotherapy and about the fluid and intensive monitoring requirements of their inpatient stay.
• Patients who have left the hospital should be educated about the possibility of seizures and should be encouraged to pursue physical therapy to maximize motor function.
• Patients with AIDS should continue to follow the antiretroviral regimen recommended by their physician.
• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Brain Cancer.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Since the clinical and neuroimaging presentation of PCNSL can be so varied and the differential diagnostic possibilities are therefore so large, no patient should be treated for PCNSL without definitive cytologic proof of diagnosis, either by vitrectomy, positive CSF cytology, or brain biopsy.
• Patients with AIDS may have coexisting infections; any change in neurologic examination findings or neuroimaging studies should be accordingly investigated broadly for the possibility of a diagnosis besides PCNSL.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. J Clin Oncol. Mar 1998;16(3):859-63. [Medline].
• Blay JY, Conroy T, Chevreau C. High-dose methotrexate for the treatment of primary cerebral lymphomas: Analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol. 1998;16:859-871.
• Buhring U, Herrlinger U, Krings T. MRI features of primary central nervous system lymphomas at presentation. Neurology. Aug 14 2001;57(3):393-6. [Medline].
• Central Brain Tumor Registry of the United States. Primary Brain Tumors in the United States 1995-1999: Statistical Report. Chicago, IL, CBTRUS, 2002-2003.
• Chamberlain MC, Kormanik PA. AIDS-related central nervous system lymphomas. J Neurooncol. Jul 1999;43(3):269-76. [Medline].
• Ciacci JD, Tellez C, VonRoenn J. Lymphoma of the central nervous system in AIDS. Semin Neurol. 1999;19(2):213-21. [Medline].
• Corboy JR, Garl PJ, Kleinschmidt-DeMasters BK. Human herpesvirus 8 DNA in CNS lymphomas from patients with and without AIDS. Neurology. Feb 1998;50(2):335-40. [Medline].
• DeAngelis LM. Primary CNS lymphoma: treatment with combined chemotherapy and radiotherapy. J Neurooncol. Jul 1999;43(3):249-57. [Medline].
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• Hoang-Xuan K, Delattre JY. Ongoing protocols for non-AIDS primary central nervous system lymphoma. J Neurooncol. Jul 1999;43(3):287-91. [Medline].
• Kessler LS, Ruiz A, Donovan Post MJ, et al. Thallium-201 brain SPECT of lymphoma in AIDS patients: pitfalls and technique optimization. Am J Neuroradiol. Jun-Jul 1998;19(6):1105-9. [Medline].
• Linnebank M, Schmidt S, Kolsch H, et al. The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma. Br J Cancer. May 17 2004;90(10):1969-71. [Medline].
• Maher EA, Fine HA. Primary CNS lymphoma. Semin Oncol. Jun 1999;26(3):346-56. [Medline].
• Miller DC, Hochberg FH, Harris NL. Pathology with clinical correlations of primary central nervous system non-Hodgkin''s lymphoma. The Massachusetts General Hospital experience 1958-1989. Cancer. Aug 15 1994;74(4):1383-97. [Medline].
• Miller DC, Hochberg FH, Harris NL, et al. Pathology with clinical correlations of primary central nervous system non-Hodgkin''s lymphoma. The Massachusetts General Hospital experience 1958-1989. Cancer. Aug 15 1994;74(4):1383-97. [Medline].
• Montesinos-Rongen M, Schmitz R, Courts C, et al. Absence of immunoglobulin class switch in primary lymphomas of the central nervous system. Am J Pathol. Jun 2005;166(6):1773-9. [Medline].
• Nasir S, DeAngelis LM. Update on the management of primary CNS lymphoma. Oncology (Huntingt). Feb 2000;14(2):228-34; discussion 237-42, 244. [Medline].
• Sugita Y, Tokunaga O, Nakashima A, Shigemori M. SHP-1 expression in primary central nervous system B-cell lymphomas in immunocompetent patients reflects maturation stage of normal B cell counterparts. Pathol Int. Sep 2004;54(9):659-66. [Medline].

Article Last Updated: Jul 10, 2006