Patterns of relapse in primary central nervous system lymphoma: inferences regarding the role of the neuro-vascular unit and monoclonal antibodies in treating occult CNS disease

Abstract

Background and purposeThe radiologic features and patterns of primary central nervous system lymphoma (PCNSL) at initial presentation are well described. High response rates can be achieved with first-line high-dose methotrexate (HD-MTX) based regimens, yet many relapse within 2 years of diagnosis. We describe the pattern of relapse and review the potential mechanisms involved in relapse.MethodsWe identified 78 consecutive patients who attained complete radiographic response (CR) during or after first-line treatment for newly diagnosed PCNSL (CD20+, diffuse large B cell type). Patients were treated with HD-MTX based regimen in conjunction with blood–brain barrier disruption (HD-MTX/BBBD); 44 subsequently relapsed. Images and medical records of these 44 consecutive patients were retrospectively reviewed. The anatomical location of enhancing lesions at initial diagnosis and at the time of relapse were identified and compared.Results37/44 patients fulfilled inclusion criteria and had new measureable enhancing lesions at relapse; the pattern and location of relapse of these 37 patients were identified. At relapse, the new enhancement was at a spatially distinct site in 30 of 37 patients. Local relapse was found only in seven patients.DiscussionUnlike gliomas, the majority of PCNSL had radiographic relapse at spatially distinct anatomical locations within the brain behind a previously intact neurovascular unit (NVU), and in few cases outside, the central nervous system (CNS). This may suggest either (1) reactivation of occult reservoirs behind an intact NVU in the CNS (or ocular) or (2) seeding from bone marrow or other extra CNS sites.ConclusionRecognizing patterns of relapse is key for early detection and may provide insight into potential mechanisms of relapse as well as help develop strategies to extend duration of complete response.

Progress in brain barriers and brain fluid research in 2017

“…Clinically, osmotic-induced blood–brain disruption is currently used to enhance delivery of anti-neoplastic agents to brain tumors [ 17 ]. An important consideration is the potential effect of the anti-neoplastic agent on normal tissue.…”

Clinical Application of Liquid Biopsy in Non-Hodgkin Lymphoma

“…With the application of high-dose methotrexate-based combination chemotherapy, the median overall survival rate of PCNSL increased from 12.5 months in the 1970s to 26 months in the 2010s ( 3 ). Similar to systemic DLBCL, approximately 50% of PCNSL patients relapse after treatment ( 4 ), and 10% to 15% of patients are primarily refractory ( 5 ). In cases of refractory or relapsed disease, the prognosis is typically poor.…”

<p>Biomarkers Reflecting The Destruction Of The Blood-Brain Barrier Are Valuable In Predicting The Risk Of Lymphomas With Central Nervous System Involvement</p>

“…Presently, the evaluating system includes imaging studies such as magnetic resonance imaging (MRI) and computed tomography (CT) scan, cytologic test, and immunophenotypic biomarkers. The subclinical CNS tumor sites may remain undetected by conventional contrast-enhanced MRI scanning behind an intact neurovascular unit or blood-cerebrospinal fluid barrier, due to contrast enhancement is related to blood-brain barrier (BBB) integrity rather than actual tumor size,6,7 Then, it is difficult to make a definitive diagnosis of lymphoma CNS metastasis 8. Based on imaging techniques, the differential diagnoses also include glioma, multiple sclerosis, acute disseminated encephalomyelitis 9,10.…”