Primary Central Nervous System Lymphoma

Introduction

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 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. Although the cells of origin are 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

Pathophysiology

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, 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.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 reportedthat 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 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 ischemic strokes and at times single or multiple focal intracerebral hemorrhage. Parasitosis, malignant lymphoma, or metastatic brain tumor often enter the differential diagnosis. Diagnosis often moves away from stroke by the steady progressive clinical course and is often confirmed by brain biopsy and histology and immunochemical staining of the biopsy specimen.
• 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. Levin et al report 100 cases of PCNS lymphoma over a period of 10 years, of which 5% were primary meningeal lymphoma.These 5 patients presented with leptomeningeal involvement as the sole manifestation and 4 of them presented with neuronal lymphomatosis affecting cranial and peripheral nerves. These manifestations can mimic other neurologic conditions such as pseudotumor cerebri or vasculitis. Meningeal or nerve biopsies were required for conclusive diagnosis. Lenarz et al report a case of primary CNS lymphoma involving both internal auditory canals that presented with sudden deafness and disequilibrium accompanied by facial and abducens nerve palsy.
• Khong et al reported a rare case of neurolymphomatosis manifesting as acute cauda equina syndrome in a 16-year-old patient.

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.

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