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L. Wang et al.
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Figure 2. Comparison of median overall survival. There is a statistically significant difference in overall survival (OS) between de novo and transformed mantle cell lymphoma (MCL) with MYC rearrangement (MYC-R) (A); MCL with MYC-R and Non-MYC-R either all patients (C), only de novo cases (D), all blastoid MCL (E) or only de novo blastoid MCL (F) were included. In all MCL patients, MYC-R group had the worst OS, MYC normal (MYC-NL) group the best OS, and MYC extra copies (MYC-EC) group laid in between (B).
phic patients were included (Figure 2E, P=0.022). However, there was no significant difference in median OS when only de novo blastoid/pleumorphic MCL patients were compared (Figure 2F, P=0.35).
Correlation of MYC expression with MYC fluorescence in situ hybridization status in mantle cell lymphoma
MYC immunohistochemical stains were performed on 51 cases of MCL, including 15 with MYC-R, 15 with MYC- EC, and 21 with MYC-NL. MYC expression level showed a much wider distribution across samples in MYC-R cyto- genetic subgroup than MYC-EC and MYC-R subgroups due to the higher level of expression. The mean percentage of cells expressing MYC protein was significantly higher in the MYC-R group than those in the MYC-EC and MYC-NL groups (50%, range, 1-100% in the MYC-R group; 13%, range, 0-55% in the MYC-EC group; and 15%, range, 0-60% in the MYC-NL group; Figure 3A, P<0.0001). There was no significant difference in the per- centage of cells expressing MYC between the MYC-EC and MYC-NL groups (P=0.71). Although MCL cases with MYC-R demonstrated protein expression at variably high levels (≥40% in 12 of 15, 80% of cases), slightly high MYC expression could occasionally occur in MCL without MYC-R. By using the 40% as a cut-off value for MYC immunohistochemistry to predict MYC-R, the sensitivity and specificity were 80% and 83% respectively.
Multivariate analysis
In order to further explore if MYC-R or MYC-EC were independent prognostic factors in MCL patients, multi- variate Cox proportional hazard analysis was performed including MYC status and other factors that often predict survival in MCL, including morphology, Ki67 rate, and MIPI score. As shown in Table 3, MYC-R but not MYC-EC was an independent prognostic factor for OS in this cohort of MCL patients.
Table 3. Multivariate analysis. Features HR
MYC-R 3.27 MYC-EC 2.375 Blastoid/Pleumorphic MCL 7.038 Ki67≥30% 1.93 High MIPI 1.217
95% CI
1.149 - 9.306
0.632 - 8.923
0.767 - 64.593
0.215 - 17.370
0.532 - 2.783
P
0.026
0.200
0.073
0.557
0.642
MYC-R: MYC rearrangement; MYC-EC: MYC extra copies; MCL: mantle cell lymphoma; MIPI: Mantle Cell Lymphoma International Prognostic Index; HR: hazard ratio; CI: Confidence Interval; P<0.05.
Patients with mantle cell lymphoma associated with MYC rearrangement versus MYC/BCL2 double hit lymphoma patients
The 27 MCL patients with MYC-R were compared with 95 patients with MYC/BCL2 DHL (Table 1), the latter group including 67 patients with de novo DHL and 28 with DHL transformed from follicular lymphoma. While many clinicopathologic features were similar between these two groups, each group had some unique features. Patients with MCL harboring MYC-R more often presented with bone marrow involvement (96% vs. 44%, P=0.0001), Ann Arbor stage IV disease (92% vs. 66%, P=0.01) and more frequent CD5 expression (71% vs. 5%, P=0.0001). In con- trast, elevated serum LDH level and more frequent CD10 and BCL6 expression were observed more often in the MYC/BCL2 DHL group (P<0.05 for all).
There was no significant difference in CR rate between MCL patients with MYC-R and patients with MYC/BCL2 DHL. Patients with MCL associated with MYC-R had an inferior median OS compared with patients with MYC/BCL2 DHL (Figure 3B, P=0.038). However, there was no significant difference in OS when patients with de novo MCL and MYC-R were compared to patients with de novo MYC/BCL2 DHL (Figure 3C, P=0.83). Since prognosis
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