Parallel evolution of two distinct lymphoid proliferations in clonal haematopoiesis

Histopathology. 2022 Apr;80(5):847-858. doi: 10.1111/his.14619. Epub 2022 Mar 1.


Aims: Angioimmunoblastic T-cell lymphoma (AITL) is genetically characterized by TET2 and DNMT3A mutations occurring in haematopoietic progenitor cells, and late events (e.g. the RHOA-G17V mutation) associated with malignant transformation. As TET2/DNMT3A-mutated progenitor cells can differentiate into multilineage progenies and give rise to both AITL and myeloid neoplasms, they may also have the potential to lead to other metachronous/synchronous neoplasms. We report two cases showing parallel evolution of two distinct potentially neoplastic lymphoid proliferations from a common mutated haematopoietic progenitor cell population.

Methods and results: Both cases presented with generalized lymphadenopathy. In case 1 (a 67-year-old female), an initial lymph node (LN) biopsy was dismissed as reactive, but a repeat biopsy showed a nodal marginal zone lymphoma (NMZL)-like proliferation with an increase in the number of T-follicular helper (TFH) cells. Immunohistochemistry, and clonality and mutational analyses by targeted sequencing of both whole tissue sections and microdissected NMZL-like lesions, demonstrated a clonal B-cell proliferation that harboured the BRAF-G469R mutation and shared TET2 and DNMT3A mutations with an underlying RHOA-G17V-mutant TFH proliferation. Review of the original LN biopsy showed histological and immunophenotypic features of AITL. In case 2 (a 66-year-old male), cytotoxic T-cell lymphoma with an increase in the number of Epstein-Barr virus-positive large B cells was diagnosed on initial biopsy. On review together with the relapsed biopsy, we identified an additional occult neoplastic TFH proliferation/smouldering AITL. Both T-cell proliferations shared TET2 and DNMT3A mutations while RHOA-G17V was confined to the smouldering AITL.

Conclusions: In addition to demonstrating diagnostic challenges, these cases expand the potential of clonal haematopoiesis in the development of different lineage neoplastic proliferations.

Keywords: TET2 and DNMT3A mutation; angioimmunoblastic T-cell lymphoma; clonal haematopoiesis; secondary lymphoid neoplasm.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • CD8 Antigens
  • Cell Proliferation
  • Clonal Hematopoiesis*
  • DNA Methyltransferase 3A / genetics
  • DNA-Binding Proteins / genetics
  • Diagnosis, Differential
  • Dioxygenases / genetics
  • Female
  • Humans
  • Immunoblastic Lymphadenopathy / diagnosis
  • Immunoblastic Lymphadenopathy / genetics*
  • Immunoblastic Lymphadenopathy / pathology*
  • Lymphoma, T-Cell / diagnosis
  • Lymphoma, T-Cell / genetics*
  • Lymphoma, T-Cell / pathology*
  • Male
  • Mutation
  • Proto-Oncogene Proteins B-raf / genetics
  • T Follicular Helper Cells / pathology
  • T-Lymphocytes, Cytotoxic / pathology
  • rhoA GTP-Binding Protein / genetics


  • CD8 Antigens
  • DNA-Binding Proteins
  • DNMT3A protein, human
  • RHOA protein, human
  • Dioxygenases
  • TET2 protein, human
  • DNA Methyltransferase 3A
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • rhoA GTP-Binding Protein