Histologic transformation of follicular lymphoma to diffuse lymphoma represents tumor progression by a single malignant B cell.

Abstract

SummaryTo investigate the clonal relationship between follicular lymphoma (FL) and transformed diffuse lymphoma (tDL), we examined the expression of tumor idiotype, immunoglobulin (Ig) gene rearrangements and sequence of Ig variable genes in paired tissue specimens. All 16 cases analyzed expressed surface immunoglobulin (slg) on both the FL and the OL, though the immunophenotype of one case of FL could not be definitively determined . In 14 of 15 cases, the surface immunophenotype was preserved ; the exception was likely secondary to a class switch from IgM to IgG. In 12 of 13 cases, antiidiotypic monoclonal antibodies prepared against the FL reacted with the paired tDL . Analysis of Ig gene rearrangements in four cases by Southern blot hybridization showed evidence of clonal relationships in all cases though concordance was not seen with all probes tested (Ctc, CX, J., PFL1, and PFL2). In the one case that had a discordant L chain rearrangement, sequence analysis of the L chain demonstrated a common mature B cell origin for both the FL and tDL . To determine whether tDL arose from one or more FL cells, the sequences of the H chain variable genes were analyzed. Individual clones of the V region gene of the FL showed a random distribution ofchanges throughout the sequence. In contrast, individual clones of the V region gene from tDL shared numerous nonrandom sequence alterations, implying a common single cell origin. In conclusion, tDL is a mature B cell and arises by transformation of a single FL cell.F ollicular low-grade non-Hodgkin's lymphoma (FL)' has a relatively indolent course with the median survival of 8-10 yr (1, 2) . However, histologic conversion to a more aggressive diffuse lymphoma (DL) is frequently observed at relapse or progression and portends a very poor survival (3, 4) . The actuarial risk of histologic conversion is 44% at 5 yr and 67% at 10 yr (2) . Histologic conversion is not monomorphic, a variety ofintermediate and high grade tumor histologies have been observed . (In this study, lymphomas will be classified according to the Working Formulation ; reference 1.) Antemortem studies suggest that the most common conversion is to diffuse large cell lymphoma (DLCL) (3, 4) though small noncleaved lymphoma (Burkitt's [SNC-B] and nonBurkitt's [SNC-nB]) (4-6) and acute lymphoblastic leukemia (ALL) have been observed (7-9) . A postmortem study (10) of 56 patients initially diagnosed with FL found that the final Abbreviations used in this paper. ALL, acute lymphoblastic leukemia ; DL, diffuse lymphoma; DLCL, diffuse large cell lymphoma; DML, diffuse mixed lymphoma; FL, follicular lymphoma; FLCL, follicular large cell lymphoma ; FML, follicular mixed lymphoma; FSCL, follicular small-cleaved cell lymphoma; LL, lymphoblastic lymphoma ; MBR, major breakpoint cluster region ; SNC-B, small noncleaved Burkitt's lymphoma; SNC-nB, small noncleaved, non-Burkitt's lymphoma ; slg, surface immunoglobulin ; tDL, transformed diffuse lymphoma ; TdT, terminal deoxynucleotidyltransferase. diagnosis was diffuse mixed ...

Molecular pathways in follicular lymphoma

“…60 However, based on analyses of sequential biopsies of a total of nine FLs, spanning significant periods, we questioned whether ICV is indeed the result of ongoing SHM. 60,[62][63][64] In only two out of these nine FLs, we observed evidence compatible with ongoing SHM, that is, ICV at both time points, accumulation of the total number of IgV H mutations over time and sustained AID expression ( Figure 1). 60,65 One FL showed no ICV at either time points, whereas six FLs showed a decrease in ICV over time, without clear accumulation of the total number of IgV H mutations.…”

“…(Figure 1). 60,[62][63][64] In three FLs, evidence was obtained for the selective outgrowth of minor subclones, that had been present already at the earliest time points. 63,66,67 Importantly, AID mRNA expression levels did not correlate with the presence nor the level of ICV in FL nor in other B-NHL such as DLBCL and BL.…”

Tumour heterogeneity and clonality – an old theme revisited

“…The initial clone (a mother clone, as it were) remains stably marked by the t(14;18) translocation present in its founder cell. As a result of ongoing somatic hypermutation in rearranged Ig genes, the B-cell tumour population nevertheless becomes heterogeneous with individual clonally related subclones tagged by specific rearranged Ig variable regions [73][74][75][76][77][78][79][80]. Serial analysis of such sequences permits the construction of a genealogical tree to portray the clonal relationship present in a lymphoid neoplasm tracing subclones which are evolutionally related, derived from a common progenitor, but which still differ because of different maturational histories.…”

Gene Expression Profile of Serial Samples of Transformed B-Cell Lymphomas

“…After transformation, FL has a variable histology and phenotype, with diffuse large B-cell lymphoma (DLBCL) being most common, followed by Burkitt-like lymphoma (Aventin et al, 1990;Yano et al, 1992) and blastic morphology (Come et al, 1980;Weiss and Warnke, 1985). Clonality studies strongly suggest that the majority of DLBCLs arising in FL are clonally related to the initial lymphoma (Matolcsy et al, 1999;Traweek et al, 1993;Zelenetz et al, 1991). The translocation (14;18)(q32;q21), the genetic hallmark of FL, is detectable in some normal individuals (Limpens et al, 1995) and is not sufficient to cause FL (Strasser et al, 1990), suggesting that additional genetic events are required (Knutsen, 1997;McDonnell and Korsmeyer, 1991).…”