CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma

Abstract

Key Points• CXCL13 and CXCL12 mediate chemotaxis of CNS lymphoma cells, and CXCL13 concentration in CSF is prognostic.• CXCL13 plus IL-10 is highly specific for the diagnosis of CNS lymphoma.Establishing the diagnosis of focal brain lesions in patients with unexplained neurologic symptoms represents a challenge. The goal of this study is to provide evidence supporting functional roles for CXC chemokine ligand (CXCL)13 and interleukin (IL)-10 in central nervous system (CNS) lymphomas and to evaluate the utility of each as prognostic and diagnostic biomarkers. We demonstrate for the first time that elevated CXCL13 concentration in cerebrospinal fluid (CSF) is prognostic and that CXCL13 and CXCL12 mediate chemotaxis of lymphoma cells isolated from CNS lymphoma lesions. Expression of the activated form of Janus kinase 1 supported a role for IL-10 in prosurvival signaling. We determined the concentration of CXCL13 and IL-10 in CSF of CNS lymphoma patients and control cohorts including inflammatory and degenerative neurologic disease in a multicenter study involving 220 patients. Bivariate elevated CXCL13 plus IL-10 was 99.3% specific for primary and secondary CNS lymphoma, with sensitivity significantly greater than reference standard CSF tests. These results identify CXCL13 and IL-10 as potentially important biomarkers of CNS lymphoma that merit further evaluation and support incorporation of CXCL13 and IL-10 into diagnostic algorithms for the workup of focal brain lesions in which lymphoma is a consideration. (Blood. 2013;121(23):4740-4748) IntroductionDetermination of the pathological basis of focal brain lesions in patients with unexplained neurologic symptoms is a major clinical challenge. Persistent symptoms or rapid neurologic decline often mandates stereotactic brain biopsy, a highly invasive procedure with a 10% to 35% rate of diagnostic failure.1-3 Moreover, many lesions are not amenable to biopsy because of small size, location in deep brain structures, risk of hemorrhage, and other comorbidities.The diagnosis of central nervous system (CNS) involvement of non-Hodgkin lymphoma is a particular challenge because of lesional response to glucocorticoids and features on magnetic resonance imaging (MRI) that are shared with other pathologies including astrocytic neoplasms, demyelination, neurosarcoid, vasculitis, infections, and leptomeningeal dissemination of systemic cancer. Although flowcytometric and cytological analysis of cerebrospinal fluid (CSF) is useful in the evaluation of leptomeningeal disease, these tests are usually insensitive to pathological processes based in deep brain structures and rarely provide information that eliminates the need for brain biopsy; the sensitivity of CSF cytological analysis in the evaluation of primary CNS lymphoma (PCNSL) is ;15%. 4Advances that facilitate diagnosis and early treatment of CNS lymphoma would likely be cost-effective, minimize repeat diagnostic CSF and MRI evaluations and brain biopsies, and also lead to improved outcomes. [5][6][7] The molecular const...

Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma

“…Our group detected elevated CXCL13 concentration in CSF of 30 PCNSL patients as compared to patients with other CNS malignancies and non-malignant CNS diseases [13]. These findings were confirmed in an analysis of 60 PCNSL and 23 SCNSL samples [14]. Viaccoz et al identified neopterin, a nonspecific marker of CNS inflammation, as possible marker to differentiate PCNSL from other brain tumours [15].…”

Absolute peripheral monocyte count at diagnosis predicts central nervous system relapse in diffuse large B-cell lymphoma

“…Peripheral monocytes, which migrate to cancer tissue and differentiate into tumor-associated macrophages, are increased in a variety of malignancies, including lymphoma. 18 The M2c subtype of monocytes can produce CXCL13 and interleukin-10, 19,20 which are known to be associated with the development of CNS lymphoma. 19 Accordingly, AMC at diagnosis in DLBCL patients may be related to CNS relapse.…”

Cerebrospinal fluid approach on neuro-oncology

“…Particular organ-specific tumor markers such as CA 15-3, CA 125, CA 19-9, CA724, AFP, NSE, Cyfra 21-1, EGFR, a-fetoprotein, b-human chorionic gonadotropin can be relatively specific for LM when elevated in CSF in the absence of markedly elevated serum levels 6,[11][12][13][14] . Nonspecific tumor markers such as molecules involved in CNS penetration (eg, matrix metalloproteinases and cathepsins), tumor cell tropism (eg, chemokines CXCL8 and CCL18) and vascular endothelial growth factor can be strong indirect indicators of LM but none are sensitive enough to improve the cytological diagnosis 3,6,11,17 . CSF antithrombin III levels have been suggested as a useful biomarker in patients with primary CNS lymphoma, but have not been evaluated in patients with lymphomatous meningitis 6,15 .…”