Molecular Genetics in the Diagnosis and Biology of Lymphoid Neoplasms

2017 Society for Hematopathology/European Association for Haematopathology Workshop Report

Megan S. Lim, MD, PhD; Nathanael G. Bailey, MD; Rebecca L. King, MD; Miguel Piris, MD


Am J Clin Pathol. 2019;152(3):277-301. 

In This Article

Developing Perspectives and Future Opportunities

One powerful application of high-throughput sequencing in lymphoma is to assess immunoglobulin or T-cell receptor loci for clonality. In contrast to conventional molecular methods, high-throughput sequencing is capable of simultaneously determining the sequence of the unique V-(D)J rearrangement contained in the lymphoma and quantifying the number of lymphoma-specific reads. This has major implications for minimal residual disease testing (which was outside of the scope of this workshop). However, the technology has the ability to compare the clonal relatedness of separate lymphoproliferations at a more granular level compared to older techniques. Case 338 illustrated an example of IGH sequencing, which revealed a high level of somatic hypermutation, favoring classification of a diagnostically difficult case as a FL rather than a MZL (case 193). Although such techniques are not by themselves required for classification, and these data could be gathered by older methods, the power of high-throughput sequencing technology to gain multiple useful pieces of information regarding the lymphoma IGH/TCR rearrangement suggests that high-throughput sequencing platforms may become the mainstay of clonality testing in the near future. Of course, clonality studies must never be interpreted in isolation, and lymphoma diagnosis requires integration of such data with the conventional morphologic and phenotypic findings to avoid misdiagnosis.

Subsequent to the workshop, two groups have proposed novel molecular classifications of DLBCL.[33,93] Both groups of investigators identified clinically relevant genetic subgroups within ABC DLBCL: a group with BCL6 translocations and NOTCH2 pathway mutations with a more favorable prognosis, and a group with MYD88 and CD79B pathway mutations with a more unfavorable prognosis. In addition, a group of GCB DLBCL with BCL2 rearrangements and epigenetic mutations (KMT2D, CREBBP, EZH2) was identified by both groups as having a more unfavorable prognosis compared to other GCB DLBCL. Applying these novel molecular classification schemes clinically is not straightforward, and further studies to confirm their clinical relevance are needed. However, these studies highlight the likely future increasing need for comprehensive genetic profiling of lymphomas.