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Vitreous cytokine levels

2003; Elsevier BV; Volume: 110; Issue: 8 Linguagem: Inglês

10.1016/s0161-6420(03)00811-x

1549-4713

Lesley A Wolf, George F. Reed, Ronald Buggage, Robert B. Nussenblatt, Chi‐Chao Chan,

Chronic Lymphocytic Leukemia Research

In 2001 we sent two letters to Ophthalmology about a controversial discussion of interleukin-10 (IL-10) and IL-6 levels in the vitreous of patients with primary intraocular lymphoma (PIOL).1Cassoux N. Merle-Beral H. Lehoang P. et al.Interleukin-10 and intraocular-central nervous system lymphoma.Ophthalmology. 2001; 108: 426-427Abstract Full Text Full Text PDF PubMed Google Scholar, 2Velez G. Buggage R. Interleukin-10 and intraocular-central nervous system lymphoma [letter].Ophthalmology. 2001; 108: 427-428Abstract Full Text Full Text PDF PubMed Google Scholar, 3Akpek E.K. Maca S.M. Christen W.G. Foster C.S. Elevated vitreous interleukin-10 level is not diagnostic of intraocular-central nervous system lymphoma.Ophthalmology. 1999; 106: 2291-2295Abstract Full Text Full Text PDF PubMed Google Scholar Here we present a relatively large series of vitreal cytokine levels from 35 PIOL patients and 64 infectious and noninfectious uveitic patients evaluated at the National Eye Institute. PIOL is a subtype of primary CNS lymphoma in which malignant cells are found initially in the eye and is usually a diffuse large B-cell lymphoma. It commonly presents as a uveitis masquerade syndrome with cellular infiltrates in the vitreous with or without subretinal infiltrates.4Chan C.C. Buggage R.R. Nussenblatt R.B. Intraocular lymphoma.Curr Opin Ophthalmol. 2002; 13: 411-418Crossref PubMed Scopus (137) Google Scholar, 5Buggage R.R. Chan C.C. Nussenblatt R.B. Ocular manifestations of central nervous system lymphoma.Curr Opin Oncol. 2001; 13 ([review]): 137-142Crossref PubMed Scopus (78) Google Scholar, 6Read R.W. Zamir E. Rao N.A. Neoplastic masquerade syndromes.Surv Ophthalmol. 2002; 47 ([review]): 81-124Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar Once suspected, a neurologic assessment, including neuroimaging and lumbar puncture with cytology of the cerebrospinal fluid, is recommended to exclude the presence of CNS disease before performing a diagnostic vitrectomy. Due to the improper handling of specimens and the difficulty in recognizing the few lymphoma cells in the vitreal samples, the possibility of a false-negative diagnostic vitrectomy is common. It should be emphasized that inaccurate or questionable results can further delay the initiation of potentially life-sparing therapy. Recent evidence has indicated the usefulness of molecular and cytokine analysis as adjunctive tools to help the pathologist differentiate between PIOL and uveitis and to support the diagnosis of PIOL.7Tuaillon N. Chan C.C. Molecular analysis of primary central nervous system and primary intraocular lymphomas.Curr Mol Med. 2001; 1 ([review]): 259-272Crossref PubMed Scopus (44) Google Scholar Elevated levels of IL-10, a growth and differentiation factor for activated B-lymphocytes,8Benjamin D. Park C.D. Sharma V. Human B cell interleukin 10 [review].Leuk Lymphoma. 1994; 12: 205-210Crossref PubMed Scopus (53) Google Scholar have been observed in the vitreous of PIOL patients.4Chan C.C. Buggage R.R. Nussenblatt R.B. Intraocular lymphoma.Curr Opin Ophthalmol. 2002; 13: 411-418Crossref PubMed Scopus (137) Google Scholar, 5Buggage R.R. Chan C.C. Nussenblatt R.B. Ocular manifestations of central nervous system lymphoma.Curr Opin Oncol. 2001; 13 ([review]): 137-142Crossref PubMed Scopus (78) Google Scholar This observation contrasts with the increased levels of vitreal IL-6 that are characteristic of ocular inflammation, as seen in patients with uveitis. In addition, studies have indicated that an IL-10 to IL-6 ratio greater than 1.0 is useful for the diagnosis of PIOL.1Cassoux N. Merle-Beral H. Lehoang P. et al.Interleukin-10 and intraocular-central nervous system lymphoma.Ophthalmology. 2001; 108: 426-427Abstract Full Text Full Text PDF PubMed Google Scholar, 2Velez G. Buggage R. Interleukin-10 and intraocular-central nervous system lymphoma [letter].Ophthalmology. 2001; 108: 427-428Abstract Full Text Full Text PDF PubMed Google Scholar We analyzed vitreous samples from 35 PIOL and 64 infectious and noninfectious uveitic patients, collected from 1993 to 2001. The diagnosis of PIOL or uveitis was based on clinical history, examination, and systemic evaluation for all patients. Disease diagnosis was then confirmed either by the presence of malignant lymphoid cells in the vitreous using cytology and/or molecular pathology in patients with PIOL or by the demonstration of only inflammatory cells in the vitreous of patients with uveitis. Some of the PIOL patients also had CNS involvement of the lymphoma. The total volume and dilution ratios of each vitreous sample varied according to the preference of the operating surgeon. All specimens were evaluated under clinical research protocols approved by the National Eye Institute institutional review board. The collected vitrectomy samples were cytocentrifuged, and the pellet was subjected for analysis by cytology and/or molecular pathology. The supernatant was separated and measured for vitreal IL-10 and IL-6 cytokine levels (pg/ml) by enzyme-linked immunosorbent assay (Endogen, Cambridge, MA). For each patient, the logarithm of the IL-10 to IL-6 ratio was calculated, and analysis, including comparison of group means by Student's t test and construction of confidence intervals, was performed on the logarithms. The results were displayed in the antilog scale as geometric mean IL-10 to IL-6 ratios (Fig 1). The fractions of PIOL and uveitis patients with an IL-10 to IL-6 ratio greater than 1.0 were calculated to determine the benefit of this cutoff point in disease diagnosis. For the PIOL group, the geometric mean IL-10 to IL-6 ratio was 5.23, with a 95% confidence interval of 2.13–12.86. The geometric mean ratio for the uveitis group was 0.23, with a 95% confidence interval of 0.15–0.36. The means significantly differed. Correct classification by the ratio greater than 1.0 cutoff rule for these patients was accomplished 74.7% of the time. The sensitivity of the cutoff rule for PIOL diagnosis was 74.3%, and the specificity was 75.0%. Because the two disease groups are complementary, these rates are reversed for diagnosis of uveitis (i.e., the sensitivity for uveitis is 75.0% and the specificity for uveitis is 74.3%). The above rates of differentiation are consistent with previous data showing that inflammatory cells produce high levels of IL-6, as seen in uveitis, whereas malignant B-lymphoid cells, such as PIOL B-cells, produce IL-10. Cytokine analysis alone cannot be used to make the diagnosis of PIOL. However, in difficult “uveitis” cases where the diagnostic vitrectomy specimen is inconclusive, a vitreal IL-10 to IL-6 ratio greater than 1.0 may prompt further evaluation to distinguish uveitis from PIOL. This may spare the patient unnecessary treatment or delays for additional diagnostic procedures.