Mutation Spectrum of Transformed Nodular Lymphocyte Predominant Hodgkin Lymphoma and Comparison with De Novo Diffuse Large B-Cell Lymphoma

Introduction:

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare disease that differs clinically and biologically from classical Hodgkin lymphoma. NLPHL is usually indolent but has a high rate of relapse as well as transformation to diffuse large B-cell lymphoma (DLBCL). Two main patterns of transformation occur, T-cell/histiocyte-rich DLBCL and more typical DLBCL. In this study, we evaluated the mutation spectrum of transformed NLPHL (tNLPHL) and compared it to a large series of de novo DLBCL.

Methods:

We identified 11 cases of transformed NLPHL from three institutions (National Cancer Institute, University of Chicago, and City of Hope). Only cases with sheets of large neoplastic cells were included in this study. Cases with concurrent NLPHL and DLBCL were macrodissected for the transformed component. A custom targeted panel with 334 genes which included the most frequently mutated genes in B-cell lymphomas was used. Library prep with paired end 100 bp sequencing and 6-10 million reads/case was performed on an Illumina HiSeq 2500. Fisher's exact test was used to compare the role of mutations in tNLPHL to a series of de novo DLBCL (n=199).

Results:

The median age at diagnosis was 37 years and the Male:Female ratio was 1.75:1. The most frequently mutated genes in tNLPHL were TET2, EP300, and TNFAIP3, while 13 additional genes are recurrently mutated including, KMT2D, MYC, NOTCH2, and CARD11, which are also seen frequently in de novo DLBCL. While there were overlapping mutations between tNLPHL and DLBCL, germinal center subtype (GCB), there were also mutations more frequently associated with activated B-cell (ABC) DLBCL (TNFAIP3, CARD11). Mutations of BCL2 (p=0.0023) and SGK1 (p=0.0015) were not seen in any cases of tNLPHL, but were frequently mutated in DLBCL, GCB (17% and 22%, respectively). Interestingly, KMT2A (18%, p=0.037), PTPN1 (18%, p=0.014), and NF1 (18%, p=0.012) were frequently mutated in tNLPHL but not commonly seen in de novo DLBCL (<5%) (Figure 1).

Conclusion:

The present study shows that the mutational spectrum in tNLPHL has similarities to de novo DLBCL, but not highly concordant to the GCB subtype. However, there were mutations that were frequently seen in tNLPHL (KMT2A, PTPN1, and NF1) but uncommonly in de novo DLBCL. These findings provide insight into the pathogenesis of tNLPHL and shows how they differ biologically from de novo DLBCL.

Figure 1

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Figure 1

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