Hematolymphoid Neoplasms

Primary CNS Lymphoma

Although primary central nervous system lymphoma (PCNSL) technically includes any lymphocytic neoplasms restricted to the central nervous system (CNS), the term is usually understood to refer to diffuse large B-cell lymphoma (DLBCL), which accounts for around 95% of PCNSL. Low-grade B-cell lymphomas are much less common in the CNS than their higher-grade counterparts, only accounting for about 3% of PCNSL in one large European series (1). The incidence of T-cell PCNSL is low in the West, only around 2%, but makes up to 17% of PCNSL cases in some Asian countries (2). Except when otherwise stated below, PCNSL here is synonymous with DLBCL of the CNS.

PCNSL accounts for approximately 2% of primary brain tumors, 6% of malignant primary brain tumors (3), and less than 1% of non-Hodgkin lymphoma diagnoses. The incidence of PCNSL has been increasing in recent years among the elderly people in some series, although no cause for it has been determined (4,5,6).

Clinical Context

The population of patients with PCNSL consists of two main groups, the immunocompromised and immunocompetent, who differ in many epidemiologic and clinical variables as well as the fundamental pathophysiology of their disease (7).

Among immunocompromised patients, PCNSL is most clearly associated with HIV/AIDS and is less common in transplant recipients and others on chronic immunosuppressive therapy, or with congenital immune defects (8,9,10). Patients in this group are generally young adults and male, roughly reflecting the population characteristics of the HIV-infected in the West (11). Rates of immunodeficiency-related PCNSL have been decreasing along with increased use of highly active antiretroviral therapy (HAART) in HIV infection.

In contrast, immunocompetent hosts of PCNSL are older (mean age, 61 years) and are evenly split between males and females (12). Pediatric cases of PCNSL are rare, though can occur in either immunocompetent or immunocompromised hosts, with overall better outcomes than adult patients (13).

Epstein–Barr virus (EBV) is important in the pathogenesis of PCNSL in the immunocompromised, one series showing a consistent presence of EBV in immunodeficient PCNSL, but not in sporadic cases (14). In AIDS patients, the term AIDS-related diffuse large B-cell lymphoma is used, whereas other EBV-related PCNSLs, typically in elderly patients, are termed EBV-positive, diffuse large B-cell lymphoma, NOS.

A small number of PCNSL are low-grade B-cell lymphomas, which differ from those that are higher grade in both prognosis and anatomic distribution. In general, low-grade lymphomas tend to arise from the dura and have an indolent course, while those of higher grade are intra-axial and aggressive. Dural lymphomas are often the marginal zone variety but can also be any other B-cell type.

The radiologic appearance of PCNSL also differs depending on whether the patient is immunocompromised. Although almost all of PCNSLs show contrast enhancement, lesions with central necrosis are much more likely in immunocompromised patients, whereas those in immunocompetent hosts are solidly contrast enhancing (15,16). In both patient groups, the lesions are located in the deep cerebral hemispheres, basal ganglia, or corpus callosum in most cases, almost always in contact with a ventricular wall and without substantial mass effect. Multiple lesions are present in fewer than half of cases (15,16). T-cell PCNSLs show similar findings, but may be more subcortical than periventricular and have a higher rate of necrosis and peripheral enhancement, even in immunocompetent hosts (17). Intraparenchymal small B-cell lesions have more variable radiologic appearance without any specific characteristic findings, while dura-based lesions have a radiologic picture similar to meningioma.

As with lymphomas elsewhere in the body, surgical intervention has no role in therapy beyond securing a tissue diagnosis, usually by stereotactic biopsy. Debulking excisions are sometimes performed on an emergent basis before the diagnosis is known, but partial resection has been associated with poorer survival (12).

Chemotherapy and radiation are the principle treatment modalities for PCNSL, yet because the CNS is impervious to many of the chemotherapeutic agents used for systemic lymphomas, many of them have limited or no effect in PCNSL. Methotrexate, when given rapidly in high doses, crosses the blood–brain barrier to provide an effective treatment, as do anthracycline agents. Radiation is also effective in treating PCNSL, often with rapid and striking reductions in tumor following treatment; however, recurrence is highly likely. Radiation monotherapy resulted in 18% 5-year survival in one series (18).

Corticosteroids also have a remarkable effect on PCNSL, sometimes causing complete radiologic remission and emptying lesional tissue of neoplastic cells. Unfortunately, the effect is temporary. Because of the dramatic effects of corticosteroid on the histologic picture of PCNSL, its use is avoided until after biopsy in suspected cases.

Survival of patients with PCNSL varies greatly depending on the patient’s immune status. A meta-analysis covering 792 cases showed median survival for immunocompromised/AIDS patients to be 2.6 months, whereas median survival for sporadic cases was 18.9 months (7). A more recent series showed a significant survival gain for PCNSL-AIDS patients treated with HAART, although median survival for the HAART-treated patients was still only 8 months (19). Age younger than 60 years is also associated with improved survival (12).

Histopathology and Immunohistochemistry

Large B-Cell Lymphoma

Intraparenchymal brain lymphomas are distributed angiocentrically, collecting in the perivascular space before infiltrating the surrounding tissue (Figure 16-1). Lymphomas, at least over short distances, may invade the brain as individual cells, creating a gradient of cellularity similar to that of infiltrating gliomas. In some cases, these perivascular gradients collide, coalescing to form a sheetlike pattern that superficially mimics other “small blue cell” malignancies. Vascular destruction is a prominent feature of CNS lymphomas, with ranks of cells invading and dissecting the vessel walls, dividing them into thin concentric strands, an effect exaggerated by reticulin staining (Figure 16-2). Necrosis is common.

The cells of PCNSL are morphologically indistinguishable from those of other DLBCLs, with scant cytoplasm, vesicular chromatin, and prominent nucleoli. Even when closely packed, there is space between individual cells and the plasma membranes are clearly separate, lacking the intercellular cohesion of carcinomas. Numerous scattered apoptotic nuclei may be present, a helpful diagnostic feature because such amounts of karyorrhectic debris are rare in other lesions.

FIGURE 16-1 Typical primary CNS large B-cell lymphoma destroying the vessel wall, filling the perivascular space and infiltrating the parenchyma.

FIGURE 16-2 Reticulin staining highlights the dissection of the vascular wall by malignant cells.

A smaller component of nonneoplastic, mature T-lymphocytes and histiocytes usually accompanies the tumor cells in PCNSL, but only rarely is this constituent prominent enough to qualify a lesion as T-cell/histiocyte-rich large B-cell lymphoma, which requires them to form the majority of the lesion, with only dispersed individual malignant B-cells (Figure 16-3) (20). This lymphoma is uncommon as a CNS primary.

FIGURE 16-3 CD20 immunostaining unmasks the malignant B-cells among nonneoplastic T-cells in this T-cell–rich large B-cell lymphoma.

FIGURE 16-4 Primary CNS T-cell lymphomas are often less cellular, more infiltrative, and more mature appearing than B-cell primary CNS lymphoma.

The typical PCNSL shows a B-cell immunophenotype, expressing Pax5, CD19, CD20, CD22, CD45, and CD79a. Further subcategorization by immunohistochemistry into stages of B-cell development is possible with antibodies against MUM1, BCL6, and CD10, although the role of this classification in PCNSL is unclear (20,21,22).

T-Cell Lymphomas

Angiocentric infiltrates are also characteristic of T-cell PCNSL, although with generally less cellular density and more infiltration than the large B-cell types (Figure 16-4) (2). The tumor cells are more often small and mature appearing in T-cell lesions, although cases of large T-cell PCNSL also occur (23). The lymphoma T-cells are immunoreactive for CD3 and may show any combination of CD4, CD5, CD7, and CD8 staining.

Low-Grade B-Cell Lymphomas

In the CNS, low-grade B-cell lymphomas are usually dura-based (Figure 16-5) and are marginal zone (“MALT-derived”) types, which comprise small B-cells that express CD20, but lack CD5, CD10, and CD23. Other types also rarely develop. Very rare intraparenchymal small B-cell lymphomas can also be of any of the many small B-cell subtypes, but are most often lymphoplasmacytic lymphoma (1), with monotonous populations of lymphocytes and plasmacytoidlymphocytes, often with scattered intranuclear immunoglobulin aggregates (Dutcher bodies), mast cells, and hemosiderin granules. As with other PCNSL, these cells are angiocentrically arranged and modestly infiltrate the surrounding brain tissue (Figure 16-6).

Plasmacytoma

Most neurosurgical specimens containing plasmacytoma are taken from bony or dural lesions in the context of multiple myeloma, which is systemic in nature. Only rarely are plasmacytomas
found in the CNS without bone marrow disease, usually as dura-based lesions (24,25). Most cases have the classic histology of small monotonous cells with eccentric round nuclei, perinuclear hof, and coarsely clumped chromatin.

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