Abstract
Abstract 2662
Diagnosis of mantle cell lymphoma (MCL) is based on cytomorphology/histology and/or immunophenotyping as well as demonstration of cyclin D1 (CCDN1) over-expression and/or presence of a t(11;14)(q13;q32)/IGH-CCND1 rearrangement. However, some cases that are considered to belong to the MCL entity lack the CCND1 over-expression and the t(11;14) translocation and thus are difficult to distinguish from other small B-cell lymphomas. This distinction is clinically very relevant, since true MCLs show an aggressive behavior while many other B-cell lymphomas do not. Recently, the over-expression of SOX11 has been demonstrated to be specific for MCLs independent of CCND1 positivity, suggesting a diagnostic role of SOX11 expression in t(11;14) negative MCLs. The prognostic role of SOX11 has been controversially discussed.
To evaluate the applicability and usefulness of SOX11 expression as a diagnostic marker for differentiation of B-cell lymphomas and to determine its impact on outcome.
In this study we analyzed 159 patients with B-cell lymphomas for SOX11 and CCND1 expression levels by quantitative real time PCR. Patients were diagnosed by cytomorphology, immunophenotyping, cytogenetics and FISH and based on these methods were categorized into t(11;14) positive MCL (n=55), t(11;14) negative mature B-cell neoplasms with an MCL-typical immunophenotype (n=37), CLL (n=29), and CLL/PL (n=38). The gene expression levels were quantified and are given relative to ABL1 gene expression. Based on a negative control cohort (n=40) comprising 20 peripheral blood and 20 bone marrow samples without evidence for malignancy the cut-off for rating the expression ratio positive was calculated by the mean value plus the threefold standard deviation and resulted in 0.29 for SOX11 and 2.9 for CCND1.
In the total cohort SOX11 expression was present in 53/159 cases (33.3%) and was strongly associated with a t(11;14) translocation (45/55, 81.8% in t(11;14) positive cases vs. 8/104, 7.7% in t(11;14) negative cases, p<0.001). Correspondingly, SOX11 expression correlated with CCND1 expression regarding positivity (45/59 (76.3%) in CCND1 positive cases vs. 8/100 (8.0 %) in CCND1 negative cases, p<0.001). Also the absolute expression levels of both genes showed a high correlation (Spearman, correlation coefficient: 0.631, p<0.001). SOX11 positive patients were younger (63.8 vs. 68.8 years; p=0.011), showed a slightly lower hemoglobin level (12.13 vs. 12.96 g/dL; p=0.04) and a lower platelet count (145,024 vs. 202,914/μl; p<0.001). A detailed analysis within the respective diagnostic subgroups revealed that SOX11 was expressed in 45/55 t(11;14) positive MCL cases (81.8%) with an overall high expression level (median: 58.9; range: 0.3–1363.8). As expected in this entity all cases were CCND1 positive. In the group of 37 t(11;14) negative B-cell neoplasms with an MCL-typical immunophenotype one case was rated positive for CCND1 expression while 6 other cases (16.2%) showed a SOX11 expression (median: 2.0; range: 0.5–322.7), suggesting that these 6 cases might be CCND1 negative MCLs. Two of the 38 CLL/PL cases were SOX11 positive but lacked CCND1 expression. In contrast, SOX11 was never rated positive in CLL cases, while 1 case showed high CCND1 expression. For a total of 107 patients the time to treatment (TTT) was available for correlation analysis. Cases with SOX11 expression had a shorter time to treatment as compared to those without (median TTT: 37 vs. 56 months, p=0.011), what was also true for CCDN1 positive (median TTT: 37 vs. 58 months, p=0.07) and t(11;14) positive cases (median TTT: 6 vs. 56 months, p=0.003).
SOX11 expression may be used in addition to CCDN1 as a marker for identification of t(11;14) positive MCLs. However, some rare B-cell neoplasms are considered to belong to the MCL but lack the t(11;14) and CCND1 over-expression. The differential diagnosis of this entity from other small B-cell lymphomas is difficult. SOX11 expression may be considered as a useful marker in addition to CCND1 expression in identification of t(11;14) negative MCL. Patients with SOX11 expression showed a shorter time to treatment, but further analyses are warranted to proof the diagnostic role of SOX11 expression as well as its prognostic impact.
Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership.
Author notes
Asterisk with author names denotes non-ASH members.
