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Parallel evolution of two distinct lymphoid proliferations in clonal haematopoiesis.

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Peer-reviewed

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Article

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Authors

Dobson, Rachel 
Chak, Pui Kwan 
Vroobel, Katherine M 
Wren, Dorte 

Abstract

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.

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Keywords

TET2 and DNMT3A mutation, angioimmunoblastic T-cell lymphoma, clonal haematopoiesis, secondary lymphoid neoplasm, Aged, CD8 Antigens, Cell Proliferation, Clonal Hematopoiesis, DNA Methyltransferase 3A, DNA-Binding Proteins, Diagnosis, Differential, Dioxygenases, Female, Humans, Immunoblastic Lymphadenopathy, Lymphoma, T-Cell, Male, Mutation, Proto-Oncogene Proteins B-raf, T Follicular Helper Cells, T-Lymphocytes, Cytotoxic, rhoA GTP-Binding Protein

Journal Title

Histopathology

Conference Name

Journal ISSN

0309-0167
1365-2559

Volume Title

Publisher

Wiley