Insights into Disease Evolution of Transformed Follicular Lymphoma Derived from Cytogenetics.

Background: Follicular lymphoma (FL) is an indolent lymphoma with a median survival of 8 years. Transformation to diffuse large B cell lymphoma (DLBCL) is a major cause of mortality. The critical events leading to transformation are still unknown. Studies looking at the clonal cytogenetic evolution of FL have implicated −6q, +7, +12, −17p, +der(18), +X and abnormalities in chromosomes 1 or 8 as poor prognostic factors.

Methods: We investigated the effect of these abnormalities and the number of alterations per tumor (NAPT) on the risk of developing transformed lymphoma (TLy) in a cohort of FL patients treated at the British Columbia Cancer Agency (BCCA) from 1983 to 2005. Karyotypes were determined on all samples by classic G banding technique. NAPT and the presence of the previously mentioned abnormalities were determined. TLy was defined as a DLBCL or Burkitt-like or composite histology (focal DLBCL with residual FL) on repeat biopsy or the presence of one of the following clinical features: rapid discordant nodal growth, sudden rise in LDH (≥2x baseline), unusual extranodal involvement or hypercalcemia. 279 FL biopsies had available karyotypes and clinical information required for this analysis.

Results: With a median follow up time of 9.5 years, 54 patients (19%) developed TLy. The mean NAPT in the initial biopsy specimen was similar whether or not TLy developed (5.3 vs 5.0). The mean NAPT in patients who developed TLy early (≤2 years) was not greater than in those who developed TLy late (> 2 years) (4.8 vs 5.2). The incidence of specific cytogenetic changes was comparable to what is reported in the literature: +X (24%), 6q- (22%), +7 (15%), +12 (10%), −17p (9%), der (18) (24%) and abnormalities in chromosomes 1 (35%) or 8 (5%). These changes did not appear to influence the risk of developing TLy nor were they more prevalent in those who developed TLy. In 12 cases where the initial and TLy karyotypes could be compared, two patterns of cytogenetic evolution emerged. In 4 cases, the initial karyotype was clearly present in the TLy karyotype, including additional secondary cytogenetic abnormalities. In the remaining 8 cases, karyotypes of the TLy lacked many of the cytogenetic abnormalities that were present in the initial biopsy, except the t(14;18) or variant. Three out of the 8 cases had a lower NAPT in the TLy. Overall, there was no correlation between the NAPT of the initial and TLy biopsies (r= −0.38 p=0.3). Amongst the 12 paired specimens, the incidence of MYC breakpoints (8q24) and P53 deletions (17p13) were greater in the TLy karyotype (25% vs 0% and 16% vs 0%, respectively).

Conclusions: The karyotype in FL at diagnosis does not influence the risk of transformation and cannot be used to predict which patients will transform early. Furthermore, there is no correlation between the NAPT in the karyotypes of the paired specimens (FL→DLBCL) even though the involvement of MYC and P53 is more prevalent in the TLy karyotypes. We hypothesize that transformation is a random event that can occur in FL cells that are less clonally evolved than those represented in the initial biopsy, analogous to a “FL stem cell”. Alternatively, the initial biopsy may not have captured the particular clone that eventually resulted in transformation, favoring subclone selection rather than clonal evolution. Newer technologies that study the genome and proteome in more detail, including the effect of the microenvironment may improve our understanding of the critical events leading to FL transformation.