Duodenal-type and nodal follicular lymphomas differ by their immune microenvironment rather than their mutation profiles

Johannes C. Hellmuth, Abner Louissaint Jr, Monika Szczepanowski, Sarah Haebe, Alessandro Pastore, Stefan Alig, Annette M. Staiger, Sylvia Hartmann, Robert Kridel, Matthew D. Ducar, Peter Koch, Martin Dreyling, Martin-Leo Hansmann, German Ott, Andreas Rosenwald, Randy D. Gascoyne, David M. Weinstock, Wolfgang Hiddemann, Wolfram Klapper and Oliver Weigert

Key Points

  • The mutational landscape of DTFL is highly related to nodal FL but harbors fewer multiple/biallelic mutations in KMT2D.

  • The immune microenvironment of DTFL is distinct from nodal FL and characterized by a chronic inflammation gene signature.

Publisher's Note: There is a Blood Commentary on this article in this issue.


Duodenal-type follicular lymphoma (DTFL) is a rare and highly indolent follicular lymphoma (FL) variant. It is morphologically and immunophenotypically indistinguishable from typical FL, characterized by restricted involvement of intestinal mucosa, and lacks extraintestinal manifestations. The molecular determinants of this distinct clinical behavior are largely unknown. Thirty-eight diagnostic biopsies from patients with DTFL were evaluated. The 10-year overall survival rate was 100% in clinically evaluable patients (n = 19). We compared the targeted mutation profile of DTFL (n = 31), limited-stage typical FL (LSTFL; n = 17), and advanced-stage typical FL (ASTFL; n = 241). The mutation frequencies of recurrently mutated genes, including CREBBP, TNFRSF14/HVEM, and EZH2 were not significantly different. However, KMT2D was less commonly mutated in DTFL (52%) and LSTFL (24%) as compared with ASTFL (79%). In ASTFL, 41% of KMT2D-mutated cases harbored multiple mutations in KMT2D, as compared with only 12% in LSTFL (P = .019) and 0% in DTFL (P < .0001). Whole exome and targeted sequencing of DTFL revealed high mutation frequencies of EEF1A1 (35%) and HVCN1 (22%). We compared the immune microenvironment gene expression signatures of DTFL (n = 8) and LSTFL (n = 7). DTFL clearly separated from LSTFL by unsupervised, hierarchical clustering of 147 chemokines and cytokines and was enriched for a chronic inflammation signature. In conclusion, the mutational landscape of DTFL is highly related to typical FL. The lower frequency of multiple mutations in KMT2D in DTFL and LSTFL indicates an increasing selection pressure for complete KMT2D loss in ASTFL pathogenesis. The highly dissimilar immune microenvironment of DTFL suggests a central role in the biology of this disease.

  • Submitted March 2, 2018.
  • Accepted August 10, 2018.
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