We are aware of published reports of ten previous cases of composite lymphoma that contained elements of FL and SLL/CLL [
2‐
6]. In two of these, the biopsy sample also contained DLBCL [
5,
6]. FL and CLL/SLL are generally considered indolent and are susceptible to transforming to more aggressive disease, most often DLBCL; in the case of CLL/SLL this occurrence is denoted “Richter’s Syndrome” [
7,
8]. In cases of transformation, the DLBCL component either evolves directly from the pre-existing FL or CLL/SLL clone or from a common precursor clone from which both the indolent lymphoma and DLBCL subsequently diverge [
7]. Therefore, initially it seemed likely that the DLBCL component in our case arose through transformation from either the FL or CLL/SLL components. Among the three reported cases (including ours) of composite lymphoma with FL, SLL and DLBCL elements, ours is the only one in which an
IGH-BCL2 fusion demonstrable by FISH was available to support the inference that the DLBCL component evolved directly from FL. This finding agrees with those of diSibio and colleagues who demonstrated the presence of an
IGH-BCL2 fusion in both the FL component of a composite lymphoma and a DLBCL that arose 15 years later [
4]. Our case is also the first in which FISH demonstrated the presence of a
MYC rearrangement in the DLBCL, but not the FL, component.
MYC rearrangements are present in 25 to 50% of transformed follicular lymphomas and most of these rearrangement events occur during transformation. [
9,
10] Especially given that
MYC rearrangements are identifiable in only 5 to 10% of de novo DLBCLs, we feel justified in suggesting that the acquisition of the
MYC rearrangement may have contributed functionally to transformation of FL to DLBCL. [
11] DLBCLs with both an
IGH-BCL2 and a
MYC rearrangement, currently denoted “high-grade B-cell lymphoma with
MYC and
BCL2 rearrangements”, are associated with poor clinical outcomes [
12]. Ours is the first reported case of composite lymphoma that includes elements of FL, CLL/SLL and high-grade B-cell lymphoma with
MYC and
BCL2 rearrangements.
Published studies have addressed the clonal relationship between the FL and SLL/CLL components in cases of composite lymphoma. Use of the polymerase chain reaction (PCR) with primers for the
IGH locus has demonstrated that the FL and CLL/SLL components contained different clonal rearrangements in 3 composite lymphomas, suggesting that these two components either arose from different clones
ab initio or diverged prior to
IGH gene rearrangement [
2,
3]. Also in support of a separate clonal origin, FISH was used to demonstrate
IGH-BCL2 fusion in the FL, but not the SLL/CLL, component in an additional 2 cases (including ours) [
4]. In contrast, Zhang and colleagues reported results from
IGH PCR that suggested clonal identity between the FL and SLL components in 3 cases of composite lymphomas [
5]. Therefore, although uncertainty persists, the bulk of available evidence currently favors a separate clonal origin for the FL and CLL/SLL components in composite lymphomas.
The relative rarity and pathological complexity of composite lymphomas makes treatment decisions challenging. In general, treatment is directed against the more aggressive component; in our case, this is high-grade B-cell lymphoma [
1]. Standard first-line treatment for DLBCL is R-CHOP [
12]. “Double-hit” status is associated with an elevated risk of treatment failure. While there has been interest in the potential utility of more intensive regimens to induce remission, such as dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R), it is not clear that these improve overall survival [
12]. Moreover, the toxicity of more intensive therapies limits their application for elderly patients or those with co-morbidities, both of which are prevalent amongst patients with composite lymphoma.