[TFH lymphoma and associated clonal hematopoiesis].

T‑follicular helper (TFH) cell lymphoma (TFHL) is a lymphoma of mature T cells with phenotypic characteristics and gene expression signature of TFH cells. The lymphoma harbors recurrent mutations of RHOAG17V, IDH2R172, TET2 and DNMT3A. Whereas RHOAG17V and IDH2R172 are almost exclusively found in this entity, TET2 and DNMT3A mutations occur in a broad variety of hematological neoplasms and are the most frequently affected genes in clonal hematopoiesis (CH). CH in humans shows a progression rate to overt hematologic neoplasia of about 0.5 to 1% per year, depending on clone size, number of mutations and affected genes. In 2018, the first case was described in which a lymphoid (TFHL) and myeloid (acute myeloid leukemia) neoplasm arose from a common mutated progenitor cell with shared mutations and additional private mutations. In recent years, further studies showed in up to 70% of patients with TFHL the occurrence of identical mutations of TET2 and/or DNMT3A in the myeloid cells, irrespective of bone marrow involvement, indicating a prominent role of CH in the pathogenesis of TFHL. In up to 18%, these patients show also additional synchronous or metachronous overt myeloid neoplasms, often with private myelodysplastic-type mutations, most often myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia. Recently, there is also evidence for two distinct lymphoid neoplasms arising from CH. TFH lymphoma cases with antecedent or concomitant hematologic neoplasm often show high variant allelic frequencies of TET2 and often more than one mutation, suggesting a role for surveillance in these patients.

Nann D ，Fend F ，Quintanilla-Martinez L 《-》

Clonal Hematopoiesis and Bone Marrow Infiltration in Patients With Follicular Helper T-Cell Lymphoma of Angioimmunoblastic Type.

Follicular helper T-cell (TFH) lymphoma harbors recurrent mutations of RHOAG17V, IDH2R172, TET2, and DNMT3A. TET2 and DNMT3A mutations are the most frequently affected genes in clonal hematopoiesis (CH). The aim of our study was to investigate the frequency of CH in bone marrow biopsies (BMB) of TFH/angioimmunoblastic T-cell lymphoma (TFH-AITL) patients and its association with myeloid neoplasms. A total of 29 BMB from 22 patients with a diagnosis of TFH-AITL were analyzed by next-generation sequencing (NGS) with a custom panel. Morphologically, 5 BMB revealed that TFH-AITL infiltrates of >5% of bone marrow (BM) cellularity confirmed in 4 cases by NGS-based T-cell clonality. IDH2R172 was demonstrated only in 1 (3%) of 29, and RHOAG17V in 2 (7%) of 29 samples. TET2 and DNMT3A were identified in 24 (83%) of 29 and 17 (59%) of 29 BMB, respectively. In the parallel lymph node the frequencies of mutations were 27% (IDH2R172), 64% (RHOAG17V), 86% (TET2), and 50% (DNMT3A). TET2 and/or DNMT3A mutations identical in lymph node and BMB were present in 18 (82%) of 22 patients, regardless of BM infiltration. In 3 cases the CH mutations were detected 13, 41, and 145 months before TFH-AITL diagnosis. Cases with TET2/DNMT3A mutations and BM variant allele frequencies >40% (7/18, 39%) showed lower blood counts. However, only low platelet count was statistically significant (P = .024). Myeloid neoplasms and/or myelodysplastic syndrome-related mutations were identified in 4 cases (4/22; 18%); all with high TET2 variant allele frequencies (>40%; P = .0114). In conclusion, CH is present in 82% of TFH-AITL and can be demonstrated up to 145 months before TFH-AITL diagnosis. NGS T-cell clonality analysis is an excellent tool to confirm TFH-AITL BM infiltration. Concurrent myeloid neoplasms were identified in 18% of the cases and were associated with TET2 mutations with high allelic burden (>40%). We demonstrated that myeloid neoplasms might occur simultaneously or precede the diagnosis of TFH lymphoma.

Harland L ，Borgmann V ，Otto F ，Overkamp M ，Bonzheim I ，Fend F ，Quintanilla-Martinez L ，Nann D ... -  《-》

Parallel evolution of two distinct lymphoid proliferations in clonal haematopoiesis.

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

Attygalle AD ，Dobson R ，Chak PK ，Vroobel KM ，Wren D ，Mugalaasi H ，Morgan Y ，Kaur M ，Ahmad R ，Chen Z ，Naresh KN ，Du MQ ... -  《-》

Clonal hematopoiesis in angioimmunoblastic T-cell lymphoma with divergent evolution to myeloid neoplasms.

Lewis NE ，Petrova-Drus K ，Huet S ，Epstein-Peterson ZD ，Gao Q ，Sigler AE ，Baik J ，Ozkaya N ，Moskowitz AJ ，Kumar A ，Horwitz SM ，Zhang Y ，Arcila ME ，Levine RL ，Roshal M ，Dogan A ，Xiao W ... -  《-》

The pathological features of angioimmunoblastic T-cell lymphomas with IDH2(R172) mutations.

Steinhilber J ，Mederake M ，Bonzheim I ，Serinsöz-Linke E ，Müller I ，Fallier-Becker P ，Lemonnier F ，Gaulard P ，Fend F ，Quintanilla-Martinez L ... -  《-》