Follicular Lymphoma with Diffuse Large B-Cell Component At Initial Diagnosis Appears to Be Associated with a Loss of BCL2 Translocation and Inferior Progression Free Survival

Based on the WHO classification, follicular lymphoma (FL) is classically divided into 3 grades. In addition, WHO also recommends that the presence of diffuse large B-cell lymphoma (DLBCL) in a FL be reported as an estimate of the proportion of DLBCL involvement. While the prognostic value of grading is well characterized in FL, the clinical significance of diffuse areas in patients with FL is less well described. Hence, this study aims to describe the morphological, molecular characteristics, and clinical significance of the diffuse component in FL.

We retrospectively studied 48 newly diagnosed follicular lymphoma with a diffuse large B-cell component (FLDC) patients between January 2000 and June 2010. Only patients with more than 10% diffuse component were included and cases with a prior history of FL with large-cell transformation were excluded. 35 of the 48 patients had fluorescence in situ hybridization (FISH) performed, using breakapart FISH probes targeting BCL2, BCL6, C-MYC, CCND1, MALT1 and IgH genes. We also investigated the significance of the proportion of diffuse component in patients with FL by percentage in the categories as follows: <25%, 25–75%, >75%.The clinical characteristics and survival outcomes of these patients were compared with 511 DLBCL patients.

A total of 48 patients diagnosed with FLDC were included in this study with a median follow-up of 33.3 months. The median age of diagnosis is 57 years (26–81) and 42 (88%) FLDC patients were of grade 3 FL. 20 patients (41%) had a high FLIPI score (3–5), while 40% had a high IPI score. All 48 patients were treated with combination chemotherapy, with 85% of patients receiving rituximab based chemotherapy. Interestingly, the results from the FISH analysis revealed that more than half (54%) of the FLDC patients did not carry the BCL2 translocation. There were 5 patients (14%) with double translocations, 2 patients with both BCL2 and BCL6 translocations and 3 patients with both BCL2 and MYC translocations. Among the FLDC patients, prognostic factors for overall survival (OS) identified by univariate Cox regression analysis were high IPI (p=0.042), presence of >75% diffuse component (p=0.031) and the absence of FISH BCL2 translocation (p=0.018). The 3 year OS was 94% in patients with the BCL2 translocation vs 58% in patients with no BCL2 translocation (p=0.043). Further analysis of the subgroup of FLDC patients without BCL2 translocation, demonstrated that the presence of BCL6 translocation did not appear to influence survival. Next, when compared to DLBCL patients, there was a significantly higher number of FLDC patients who were more likely to be male (75% vs 54%, p=0.016), stage III-IV disease (75% vs 47%, p=0.001), but more patients received rituximab-based chemotherapy (81% vs 64%, p=0.049). There were however no significant difference in the two groups in the median age of diagnosis and IPI score. The 3-year progression free survival (PFS) of FLDC patients is 48% compared to 67% DLBCL, although the difference was not significant (p=0.128). The 3-year OS was however similar in both groups.

FLDC is an aggressive entity with the majority of patients presenting with grade 3 FL, more advanced disease and with a 3-year PFS of 48%. More than 50% of patients demonstrated a loss of BCL2 translocation and is associated with a poorer prognosis. A diffuse component of > 75% also portends an inferior outcome. Lastly, the IPI appears to be a more useful prognostic tool than FLIPI in patients with FLDC.

No relevant conflicts of interest to declare.