How I treat CNS lymphomas

Abstract

The pathogenesis of primary and secondary central nervous system (CNS) lymphoma poses a unique set of diagnostic, prognostic, and therapeutic challenges. During the past 10 years, there has been significant progress in the elucidation of the molecular properties of CNS lymphomas and their microenvironment, as well as evolution in the development of novel treatment strategies. Although a CNS lymphoma diagnosis was once assumed to be uniformly associated with a dismal prognosis, it is now reasonable to anticipate long-term survival, and possibly a cure, for a significant fraction of CNS lymphoma patients. The pathogenesis of CNS lymphomas affects multiple compartments within the neuroaxis, and proper treatment of the CNS lymphoma patient requires a multidisciplinary team with expertise not only in hematology/oncology but also in neurology, neuroradiology, neurosurgery, clinical neuropsychology, ophthalmology, pathology, and radiation oncology. Given the evolving principles of management and the evidence for improvements in survival, our goal is to provide an overview of current knowledge regarding the pathogenesis of CNS lymphomas and to highlight promising strategies that we believe to be most effective in establishing diagnosis, staging, and therapeutic management.

Figure 1

Pathologic features of PCNSL. (A) Diffuse, large B-cell lymphoma (DLBCL) involving the left parietal lobe and basal ganglia exhibits marked mass effect, subependymal spread, and invasion of the lateral ventricle at relapse, upon progression with HD-MTX and rituximab-based chemotherapy. (Courtesy Ray Sobel, MD, Stanford University School of Medicine). (B) DLBCL cells exhibiting an angiotropic growth pattern in a diagnostic specimen of PCNSL (hematoxylin and eosin [H&E] stain, original magnification ×100). (C) Invasive growth of DLBCL cells along the cerebral vasculature in PCNSL (H&E, original magnification ×200). (D) High expression of MYC by DLBCL cells in a diagnostic specimen of PCNSL, as demonstrated by immunohistochemistry (original magnification ×400). (Courtesy Eric Hsi, MD, Cleveland Clinic).

Figure 2

Characteristic radiographic features of PCNSL on magnetic resonance imaging. (A) A T1 axial, postgadolinium image depicts a periventricular contrast-enhancing lesion with near-uniform contrast enhancement, vasogenic edema and mass effect, in displacement of the lateral ventricles. Lesional contrast enhancement using MRI is used for response assessment. (B) A flair signal abnormality demonstrates the extent of vasogenic edema. (Courtesy Soonmee Cha, MD, University of California–San Francisco).

Figure 3

Features of intraocular lymphoma. (A) Slit-lamp evaluation demonstrating advanced intraocular lymphoma with optic disc swelling, vasculitis, and subretinal and retinal infiltrates. (B) Optical coherence tomography demonstrating a nodular hyper-reflective lesion (arrow) at the retinal pigment epithelium and subretinal space. (Courtesty Paul Stewart, MD, University of California–San Francisco).

Figure 4

How I treat PCNSL. In the diagnostic work-up, an MRI of the spine (± gadolinium) 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 for each patient, 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.

Figure 5

Progress in the treatment of PCNSL. Comparison of outcomes for newly diagnosed PCNSL in 2 multicenter cooperative group clinical trials. (A) Combined modality therapy with whole-brain radiotherapy in RTOG-9310 resulted in median progression-free survival of 2 years, with a significant rate of disease progression beyond 2 years. (B) Immunochemotherapy with rituximab plus intensive consolidation—CALGB (Alliance) 50202—resulted in a median progression-free survival of 4 years with evidence for a stable plateau in the survival curve. (C) Progression-free survival was particularly encouraging for the 65% of patients who received both induction plus consolidation treatment modules of CALGB (Alliance) 50202.