Early thymic precursor‐like lymphomatous presentation of the ETV 6‐NCOA 2 translocationписьмо
Аннотация: A 5 year-old, previously healthy boy presented with fever and lymph node enlargement. Clinical examination revealed hepatosplenomegaly, cervical, axillary and inguinal adenopathy and enlarged non-exudative tonsils. He had significant Epstein–Barr virus (EBV) viraemia at 11900 copies/ml. EBV serology was positive, with anti-viral capsid antigen (VCA) IgG levels of >700 u/ml, while anti-VCA IgM were negative, consistent with subacute or recent infection. There was mild pancytopaenia, with Hb of 109 g/l, whit blood cell count of 3·86 × 109/l and a platelet count of 220 × 109/l. Serum lactate dehydrogenase was elevated at 860 iu/l (normal range 120–300 iu/l), but all other biochemical investigations were normal apart from minimal transaminitis (aspartate transaminase 66 iu/l, alanine transaminase 83 iu/l). The atypical clinical presentation and discovery of extensive large cervical, intra-thoracic and intra-abdominal adenopathy by ultrasound, computed tomography and 18F- fluorodeoxyglucose positron emission tomography (Fig 1A) prompted further investigation. Immunohistological analysis of an inguinal lymph node (Fig 1B) showed replacement of the normal architecture with an infiltrate of medium to large T lymphoid cells with CD45, CD5, CD56 and weak CD3 expression. Staining for CD4, CD8, CD1a, CD30, CD20 and EBV/LMP1 was negative. Immunophenotypic flow cytometric analysis of the nodal aspirate confirmed the immature T-cell population (cCD3+, CD7+, CD2-, sCD3-, CD5 low, CD1a-, CD4-, CD8-), which co-expressed haematopoietic stem cell (HSC) and myeloid antigens (CD34, HLA-DR, CD38, CD123 and CD33). A minority of cells were positive for TdT. Biallelic incomplete TRDD2-TRDD3 rearrangements were identified by polymerase chain reaction (PCR), but no clonal rearrangements of TRG, TRB or IGH were detected (Fig 1C). Bone marrow (BM) aspiration revealed 3% malignant infiltration with phenotypically identical immature cells, consistent with a diagnosis of Stage IV T-lymphoblastic lymphoma (T-LBL). Karyotypic analyses of lymph node and BM samples identified a t(5;11)(p1?5;q22) rearrangement involving the ATM gene (data not shown), and a t(8;12)(q13·3;p13) translocation (Fig 1D, upper panel). These anomalies were present in the same clone in 17/20 examined metaphases. The latter translocation prompted us to test for the ETV6-NCOA2 fusion that has previously been reported in T-acute lymphoblastic leukaemia (ALL) (Strehl et al, 2008; Homminga et al, 2011; Zhou et al, 2012). Interphase fluorescent in situ hybridization (FISH) of BM tissue revealed co-localization of the ETV6 and NCOA2 genes in 80% of cells (Fig 1D, lower panel), and expression of the fusion transcript was confirmed by reverse transcription-PCR and direct sequencing (Fig 1E). Treatment was commenced according to the Euro-LB02 LBL protocol, with achievement of complete remission and post-induction negativity (<10−4) for minimal residual disease by both flow cytometry and ETV6-NCOA2 transcript quantification. The patient has maintained an excellent clinical response and, at his last assessment, had remained in molecular remission for 8 months since the end of maintenance treatment, 3 years after diagnosis. To our knowledge, the ETV6-NCOA2 rearrangement has been reported in 8 published cases of T-ALL (Strehl et al, 2008; Homminga et al, 2011; Zhou et al, 2012), but never in association with LBL. The involved exons in this case (Fig 1E) were translocated in only 1/6 cases where breakpoints were analysed (Strehl et al, 2008). We performed PCR screening for the translocation in a further 91 cases of T-LBL (57 adults and 34 children), using primers that are predicted to identify all published ETV6-NCOA2 fusions, but no additional cases were identified (data not shown). Translocations proximate to the ETV6 and NCOA2 loci, i.e. t(8;12)(q13;p13), have additionally been reported in B-ALL (Pui et al, 1987), acute myeloid leukaemia (Yamamoto et al, 2002) and T-ALL (Schneider et al, 2000), albeit in the absence of molecular confirmation of ETV6-NCOA2 fusion. In the single reported series where immunophenotype was reported in detail, co-occurrence of lymphoid and myeloid antigens was common, and frequently fulfilled the diagnostic criteria for biphenotypic leukaemia (Strehl et al, 2008). Similarly, the case described here demonstrated weak or absent expression of several T-cell markers (CD2, CD5, CD1a, CD4, CD8) and positivity for HSC and myeloid antigens (CD34, HLA-DR, CD33), which, in a leukaemic context, would fulfil the immunophenotypic criteria for early thymic precursor (ETP) ALL. Taken together, it is likely that the translocation occurs preferentially in an early haematopoietic progenitor in which lineage commitment has not yet taken place. The presence of a mediastinal mass in this case is compatible with malignant transformation of an immature thymic precursor, although BM positivity for ETV6-NCOA2+ cells may indicate that the translocation arose in a multipotent marrow progenitor that disseminated and proliferated rapidly in secondary lymphoid organs. ETV6 is promiscuously rearranged in acute leukaemia, and oncogenesis and disease biology is intimately linked to subversion of translocation partner function (De Braekeleer et al, 2012). While ETV6-RUNX1 is firmly associated with excellent prognosis in B-ALL, prediction of the outcome of other ETV6-rearranged subgroups is limited by a paucity of described cases. ETV6-NCOA2 has been reported to be associated with good treatment responses, although usually in the context of additional favourable variables like NOTCH1 mutation (Strehl et al, 2008). The good outcome in this case was achieved in spite of the absence of biallelic deletion (ABD) of TRG and germline status for NOTCH1/FBXW7, both of which we have previously shown to confer poor prognosis in paediatric T-LBL (Callens et al, 2012), and also despite the presence of an ATM anomaly, which is frequently associated with poor treatment responses in haematological malignancies (Reviewed in Choi et al, 2016). Of note, the lymphoma cells in this case had very low levels of HOXA expression (data not shown), which we have shown to predict good prognosis in ETP-ALL (Bond et al, 2016), suggesting that the possibility that HOXA levels might similarly correlate with outcome in ETP-like LBL should be further investigated. JB was supported by a Kay Kendall Leukaemia Fund Intermediate Research Fellowship. The Macintyre laboratory is supported by the Association Laurette Fugain and the INCa/DGOS CARAMELE Translational Research and PhD programs. JB, ATo, NN, ATr, VDC, PEB, and IRW performed and interpreted diagnostic investigations. ST, NG and JLS provided clinical care and/or interpreted clinical data. JB, ATo, JLS and EAM analysed and collated data and wrote the manuscript. The authors report no conflict of interest.
Год издания: 2017
Авторы: Jonathan Bond, Aurore Touzart, Nathalie Nadal, Amélie Trinquand, Sandrine Thouvenin, Vanessa Da Cruz, Pierre‐Emmanuel Bonté, Isabelle Radford‐Weiss, Nathalie Garnier, Jean‐Louis Stéphan, Elizabeth Macintyre
Издательство: Wiley
Источник: British Journal of Haematology
Ключевые слова: Lymphoma Diagnosis and Treatment, CNS Lymphoma Diagnosis and Treatment, Cardiac tumors and thrombi
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Открытый доступ: bronze
Том: 181
Выпуск: 3
Страницы: 392–394