Primary central nervous system lymphoma

Abstract

Primary central nervous system lymphoma (PCNSL) is a diffuse large B cell lymphoma in which the brain, spinal cord, leptomeninges and/or eyes are exclusive sites of disease. Pathophysiology is incompletely understood, although a central role seems to comprise immunoglobulins binding to self-proteins expressed in the central nervous system (CNS) and alterations of genes involved in B cell receptor, Toll-like receptor and NF-κB signalling. Other factors such as T cells, macrophages or microglia, endothelial cells, chemokines, and interleukins, probably also have important roles. Clinical presentation varies depending on the involved regions of the CNS. Standard of care includes methotrexate-based polychemotherapy followed by age-tailored thiotepa-based conditioned autologous stem cell transplantation and, in patients unsuitable for such treatment, consolidation with whole-brain radiotherapy or single-drug maintenance. Personalized treatment, primary radiotherapy and only supportive care should be considered in unfit, frail patients. Despite available treatments, 15-25% of patients do not respond to chemotherapy and 25-50% relapse after initial response. Relapse rates are higher in older patients, although the prognosis of patients experiencing relapse is poor independent of age. Further research is needed to identify diagnostic biomarkers, treatments with higher efficacy and less neurotoxicity, strategies to improve the penetration of drugs into the CNS, and roles of other therapies such as immunotherapies and adoptive cell therapies.

Figure 1:. PCNSL histopathology.

A) Large lymphoid cells (blue arrowheads) may grow in perivascular space, forming perivascular cuffing. B) CD20 positive large B-cell here display a diffuse growth pattern. In addition to the classical interstitial distribution of reactive T cells, PCNSL exhibit, in one third of cases, a perivascular rim of small reactiveT lymphocytes (so called ‘reactive perivascular T cell infiltrate’, RPVI) is recognized (red arrows). RPVI may occur alone or interposed between blood vessel wall and perivascular lymphomatous cells and does not stain with anti-CD20 (Figure C, black arrows), whereas it is identified by anti-CD3 stain (Figure D, black arrows). V= vascular lumen.

Figure 2:. Biological and molecular propertiers of microenvironment in PCNSL.

The interaction of tumor cells in PCNSL with microenviroment involves several cells (mainly T-cells, endothelial cells, macrophages, microglia, and astrocytes, as well as different receptors, cytokines and chemokines

Figure 3:. Biological and molecular propertiers of neoplastic cells in PCNSL.

Molecular features intrinsic to neoplastic cells in PCNSL involve receptors, intracytoplasmic pathways as well as a variety of mechanism including cell cyle, cell differentiation, NF-kB signaling, somatic hypermutations, and epigenetics.

Figure 4:. Intraocular infiltration.

Fundoscopy shows tumoral infiltration of the retina and retinal hemorrages (arrows) in a patient with primary cerebral lymphoma.

Figure 5:. MRI findings in a patient with Primary CNS Lymphoma.

T2-Weighted MRI shows a relatively T2W hypointense mass (panel A, black arrows) centered along the midline within the corpus callosum, extending into the left basal ganglia, which is distinct from the hyperintensity of the extensive surrounding non-tumoral vasogenic edema (panel A, white arrows). The mass demonstrates homogeneous diffuse contrast enhancement on post-contrast T1W imaging (panel B, yellow arrows), which is confirmed on T1W pre-contrast imaging (panel C, arrows). Moreover, the mass shows characteristic restricted diffusion seen as bright signal on diffusion trace imaging (panel D, arrows) and confirmed as hypointensity on maps of Apparent Diffusion Coefficient (ADC) (panel E, black arrows). Restricted diffusion has been attributed to paucity of extracellular fluid relative to highly cellular content of these tumors. Of note, the ADC values of non-tumoral vasogenic edema are seen as hyperintense regions on ADC maps, presumably due to greater proportion of extracellullar fluid relative to tissue cellularity (panel E, white arrows). On Dynamic Susceptibility Contrast MRI maps of relative cerebral blood volume (rCBV), the mass shows areas of mild to moderately (> 2.0) elevated rCBV (panel F, black arrow), with a prominent enhancing subependymal vein (arrow).

Figure 6:. Therapeutic flow-chart for patients with newly-diagnosed PCNSL.

A) Suitability for chemotherapy and intensified treatment (ASCT) is a complex decision that is based on several factors, including age, performance status, comorbidity, organ function, frailty, and risk of neurotoxicity among others. The clinical experience of the treating physician and patient’s wishes have important roles on treatment choice. B) Consolidation with reduced-dose whole-brain radiotherapy is an option in elderly patients with disease responsive to induction therapy- ASCT= myeloablative chemotherapy supported by autologous stem-cell transplantation; BSC= best supportive care; CR= complete remission; HD-ARAC= high-dose cytarabine; HD-MTX= high-dose methotrexate; PD= progressive disease; PR= partial response; SD= stable disease; WBRT= whole-brain radiotherapy.