49. Cryptic Triple Hit Lymphoma: What's hiding in those chromosomes? A chromosome, FISH and microarray story

High-grade B-cell lymphoma with concurrent MYC, BCL2, and BCL6 rearrangements (i.e. Triple Hit Lymphoma (TH)) is an aggressive lymphoma generally detected by conventional cytogenetics and/or FISH. We present a patient referred for high grade diffuse large B-cell lymphoma with a complex karyotype. The diagnosis was consistent with follicular lymphoma and clonal evolution, based only on the karyotype analysis. Dual fusion and breakapart (BAP) FISH strategies and microarray testing were required to diagnosis TH lymphoma. The karyotype included a t(14;18) with an extra derivative 14 (no normal 14), a t(3;22)(q27;q11.2), a t(2;6) and trisomy 8. IGH/BCL2 FISH identified three fusions, consistent with the novel double derivative (14)t(14;18) and derivative 18. BCL2 -BAP FISH showed one germline fusion, a 3’ signal and two 5’ signals rather than the typical evolution related extra 3’ signal, but consistent with the double derivative 14. MYC-BAP FISH showed three un-rearranged fusions discordant with the double fusion IGH/MYC result. This apparent incongruence could be explained by an IGH insertion into MYC which was confirmed by metaphase FISH. The BCL6 FISH was also atypical with 2 germ line fusions and a small extra 5’ BCL6 signal. Since the microarray showed no 3q27 gain, a balanced rearrangement between the 5’BCL6 promotor and the lambda-light gene at 22q11.2 was concluded. Copy neutral LOH (CN-LOH) of 14q32.13->qter in the array analysis (spanning IGH) supports mitotic recombination based clonal evolution for the novel double derivative 14, consistent with a reversal of the common oncogenic fusion derivative. A second CN-LOH region was observed spanning distal 6p, although the driver gene for that evolution is not clear. In summary, the TH would have been missed without multiple disciplinary ancillary testing, highlighting their importance in accurately evaluating complex clones in facilitating optimal patient care and management.