The Challenge of Primary Central Nervous System Lymphoma

Abstract

Primary central nervous system (CNS) lymphoma is a challenging subtypes of aggressive non-Hodgkin lymphoma. Emerging clinical data suggest that optimized outcomes are achieved with dose-intensive CNS-penetrant chemotherapy and avoiding whole brain radiotherapy. Anti-CD20 antibody-based immunotherapy as a component of high-dose methotrexate-based induction programs may contribute to improved outcomes. An accumulation of insights into the molecular and cellular basis of disease pathogenesis is providing a foundation for the generation of molecular tools to facilitate diagnosis as well as a roadmap for integration of targeted therapy within the developing therapeutic armamentarium for this challenging brain tumor.

Keywords: Aggressive lymphoma; Brain tumor; High-dose chemotherapy; NF-κB; Primary CNS lymphoma.

Figure 1

Pathologic features of PCNSL. (A) Diffuse, large B-cell lymphoma (DLBCL) involving the left parietal lobe and basal ganglia with significant mass effect, subependymal spread, and invasion of the lateral ventricle, upon progression with HD-MTX and rituximab-based chemotherapy. (B) High expression of MUM1 by diffuse large B-cell lymphoma cells in a diagnostic specimen of PCNSL, as demonstrated by immunohistochemistry (B) Cytology of diffuse large B-cell lymphoma in cerebrospinal fluid in recurrent PCNSL. (C) Fluorescein angiography demonstrates classic ‘leopard spots’ in intraocular lymphoma. (Courtesy of Ray Sobel, MD, Stanford University School of Medicine, Stanford, CA.)

Figure 2. NF-kB Activation in Primary CNS Lymphoma

NF-kB transcriptional activation is regulated by multiple signals in PCNSL, including the MYD88/IRAK1/4 complex and the B cell receptor (BCR) complex consisting of CD79A and B and SYK tyrosine kinase. Activation of IRAK1 and 4 kinases via the oncogenic mutation of MYD88 at L265P impacts ~50% of PCNSL cases. MYD88 is an adapter protein that mediates toll-like receptor (TLR) and interleukin-1 receptor signaling. In addition, chronic active signaling via the BCR involving SYK and BTK also potentiates NF-kB activation. Activating mutations involving CD79B, a component of the BCR, as well as CARD11, a mediator of BCR signaling, are each present in ~15% of cases and result in NF-kB activation.

Figure 3

IL-10 Expression in CNS Lymphomas. Absent expression in normal brain (A) with strong expression of IL-10 by lymphoma cells in PCNSL (B), as demonstrated by immunohistochemistry. (X1000). (C) Quantitative RT-PCR demonstrates markedly increased expression of IL-10 in diagnostic specimens of PCNSL (N=23) compared with reactive tonsils and normal brain. The average IL-10 expression was higher in PCNSL compared to 9 cases of nodal DLBCL of which 7 were of germinal center phenotype. (D) Mean CSF IL-10 protein is 70-fold higher in patients with PCNSL and SCNSL compared to neuro-inflammatory conditions and other brain tumors (p< 2.3 X 10⁻⁵). CSF concentration of IL-10 was highest in relapsed cases.

Figure 4

(A) IL-10 concentration in CSF correlates with disease course in patients with recurrent CNS lymphomas that are treated with rituximab plus methotrexate (representative of six consecutive cases). (B) Cytological appearance of lymphoma cells in CSF at baseline and persistent disease at completion of intraventricular therapy with rituximab plus methotrexate. (From Rubenstein, J.L., et al. CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood 2013;121:4740–4748; with permission.)

Figure 5

MRI features of PCNSL in two patients at diagnosis (A). MRI depicts homogeneously enhancing mass with vasogeneic edema. (B). Normal appearing MRI of patient with progressive neurologic symptoms who was aggressively treated with steroids before a diagnosis could be elicited. Four repeat CSF collections and one brain biopsy were non-diagnostic and the diagnosis of disseminated PCNSL was made at autopsy. Notably, the CSF of each patient contained elevated concentrations of CXCL13 and IL-10, highly specific biomarkers that facilitate diagnosis of PCNSL. (From Rubenstein, J.L., et al. CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood 2013;121:4740–4748; with permission.)

Figure 6. Outcomes with intensive chemotherapy and immunotherapy in newly-diagnosed primary central nervous system lymphoma, without whole brain radiotherapy: CALGB (Alliance) 50202)

Outcome for all CALGB 50202 patients; y-axis refers to cumulative probability of event. (A) Progression-free survival (PFS) for all patients. The 2-year PFS was 59%. (B) PFS for those patients who attained a complete response with MT- R (high-dose methotrexate, temozolomide, rituximab) induction and received EA (etoposide cytararbine) consolidation (n = 27). (C) PFS was similar for patients aged >60 years (n = 23) and for younger patients (n = 21; P = 0_48). (D) There was a trend between shorter PFS and highest International Extranodal Lymphoma Study Group (IELSG) risk score of 4–5 (P = 0_16). (From Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD & Kaplan LD. Intensive Chemotherapy and Immunotherapy in Patients With Newly Diagnosed Primary CNS Lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 31 (2013), 3061–3068; with permission.)

Figure 7. Approach to Treatment of Newly Diagnosed Primary CNS Lymphoma

In the diagnostic work-up, an MRI of the spine may be useful if warranted by neurologic symptoms or if CSF analysis is contraindicated. Ultrasonography of the testes is indicated for older male patients with CNS involvement of lymphoma in which testes coinvolvement is suspected on clinical and/or radiographic grounds. The value of a positron emission tomography scan in this setting is not established. Although the schedule of Decadron taper should be individualized, we recommend a planned taper to be completed within 2 to 3 weeks of diagnosis, between the first and second courses of HD-MTX. Therapeutic options for indolent lymphomas that involve the CNS or dura include rituximab, fludarabine, involved-field irradiation, and HD-MTX for CNS involvement of chronic lymphocytic leukemia/small lymphocytic leukemia. For newly diagnosed patients who are not candidates for HD-MTX, in most cases we recommend a trial of temozolomide and rituximab and/or strategies that use high-dose chemotherapy, before consideration of using whole-brain irradiation. ASCT, autologous stem cell transplant; CR, complete response; EA, etoposide-cytarabine; HSV, herpes simplex virus; MT-R, combination HD-MTX, temozolomide, and rituximab (rituximab is omitted for T-cell lymphomas); PCP, Pneumocytis jiroveci pneumonia; PD, progressive disease; PR, partial response; SD, stable disease; WBRT, whole-brain radiotherapy. (Originally published by the American Society of Hematology. (From Rubenstein et al., How I treat CNS lymphomas. Blood 20134;122:2318–2330; with permission.)