Cerebrospinal fluid interleukin-10 is a potentially useful biomarker in immunocompetent primary central nervous system lymphoma (PCNSL)

Abstract

The diagnosis of primary central nervous system lymphoma (PCNSL) by radiographical examination is often difficult because of its similarity to other brain tumors. To test whether interleukin-10 (IL-10) and IL-6 can be used to distinguish PCNSL from other brain tumors that are radiographically similar, cerebrospinal fluid (CSF) levels of IL-10 and IL-6 were measured in 66 patients with intracranial tumors (PCNSLs: 26 cases; other brain tumors: 40 cases). In the patients with PCNSLs, the median CSF levels of IL-10 and IL-6 were 27 pg/mL and 5.4 pg/mL, respectively. The CSF IL-10 and IL-6 levels were significantly higher in PCNSLs than in the other brain tumors. To validate the diagnostic value of CSF IL-10 in PCNSL, we prospectively examined 24 patients with brain lesions that were suspected to be PCNSL. We observed that the CSF IL-10 levels were significantly higher in PCNSLs than in other brain tumors. At an IL-10 cutoff level of 9.5 pg/mL, the sensitivity and specificity were 71.0% and 100%, respectively. After therapy, the CSF IL-10 levels were decreased in all patients and were increased at relapse in most of these patients. Immunohistochemically, all PCNSLs, except for 1 unclassified PCNSL, expressed both IL-10 and IL-10 receptor-A. In the patients with high CSF IL-10, IL-10 expression levels in tumor were relatively higher, compared with low CSF IL-10; however, there was no significant difference between these groups. In addition, elevated CSF level of IL-10 was significantly associated with having a shorter progression-free survival (hazard ratio, 3.37; 95% confidence interval, 0.985-11.528; log-rank, P= .038). These results indicate that the CSF level of IL-10 may be a useful diagnostic and prognostic biomarker in patients with PCNSLs.

Fig. 1.

Pretherapy CSF levels of IL-10, IL-6, β2-M, and sIL-2R in PCNSL and other brain tumor types. The difference between PCNSL and other brain tumor types was statistically significant (^##P< .001, ^#P< .05, Mann–Whitney U test). PCNSL, primary CNS lymphoma; OBT, other brain tumors.

Fig. 2.

Receiver-operator characteristic (ROC) curves of the CSF IL-10, IL-6, β2-M, and sIL-2R levels (IL-10: sensitivity 0.71, specificity 1.00 at 9.5 pg/mL; IL-6: sensitivity 0.77, specificity 0.63 at 4.0 pg/mL; β2-M: sensitivity 0.90, specificity 0.88 at 2056 μg/L; sIL-2R: sensitivity 0.57, specificity 0.81 at 77 U/mL).

Fig. 3.

Changes of the CSF levels of IL-10 and IL-6 from pretreatment to posttreatment in the patients with PCNSLs.

Fig. 4.

The relationship between the state of the tumor and the CSF concentrations of IL-10 and IL-6. (Case 2) (A) Pre-treatment. Brain MRI revealed enhanced lesions in the right occipital lobe and the corpus callosum. At this time, IL-10 and IL-6 concentration were 1090 pg/mL and 16.2 pg/mL, respectively. (B) Spontaneous regression. Three weeks later, (A) the tumor rapidly regressed without any treatment. CSF concentrations of IL-10 and IL-6 fell to 113 pg/mL and 2.8 pg/mL, respectively. (C) Tumor re-progression. After spontaneous regression, the tumors developed again in the bilateral frontal lobes. CSF concentrations of IL-10 and IL-6 were elevated at 675 pg/mL and 8.3 pg/mL, respectively. (D) Post-treatment. After chemo-radiotherapy, the tumors disappeared (complete response) and CSF IL-10 and IL-6 levels fell to <2 pg/mL and 1.3 pg/mL, respectively.

Fig. 5.

Immunohistochemistry of IL-10, IL-10RA, and Bcl-2 in 3 patients with PCNSL. Upper panels: Patient 2 displays a very high CSF concentration of IL-10. Expression levels of IL-10, IL-10R, and Bcl-2 were all strong (3+). Middle panels: Patient 5 displays high CSF concentration of IL-10. Expression levels of IL-10, IL-10R, and Bcl-2 were moderate (2+), moderate (2+), weak (1+), respectively. Lower panels: Patient 19 displays a CSF concentration of IL-10 that is below the detection limit. Expression levels of IL-10, IL-10R, and Bcl-2 were moderate (2+), strong (3+), and weak (1+), respectively. (Original magnification: 400×).

Fig. 6.

(A) Comparison of Kaplan–Meier PFS curves according to CSF IL-10 levels (low IL-10: <28 pg/mL (n = 14), high IL-10: ≥28 pg/mL (n = 14)) (log-rank test). (B) Comparison of Kaplan-Meier OS curves according to CSF IL-10 levels (low IL-10: <28 pg/mL (n = 14), high IL-10: ≥28 pg/mL (n = 14)) (log-rank test).