T Lymphoblastic Lymphoma (T-LL): One or Two Diseases?.

T-LL are rare immature T lymphomas defined by frequent mediastinal involvement, expression of cCD3 and/or CD2 and <25% bone marrow involvement. Their prognosis is strikingly different in children (5 yr. survival approximately 90%) compared to adults (approximately 55%), but no reliable prognostic indicators exist. The extent to which T-LL differ biologically from T-ALL is not known. To adress this question, we performed paraffin TMA immunophenotyping, BIOMED 2 TCR genotyping (Southern and PCR) and RQ-PCR quantification of pTa, RAG1, HOXA5/A9, TLX1/3, LMO1/2, LYL1, TAL1, SIL-TAL, CALM-AF10 and NUP214-ABL (fusion) transcripts in a retrospective series of 44 cCD3+ T-LL (12 aged<16 y; 32 adults; 25 lymphnodes, 13 mediastinal biopsies and 6 pleural effusions). Mediastinal imaging was used to distinguish cases with bulky thymic masses from those with predominant lymphnode involvement. We used detection of TCRB VDJ clonal rearrangement to identify two distinct categories of T-LL: TCRB VDJ positive cases (n=29) and TCRB VDJ negative cases (n=15). TCRB VDJ+ expressed CD2 70%, CD5 95%, CD1a 45%, CD4/8 DP 55%, CD8 SP 25%, CD34 10 % and CD117 18%, pTa and RAG1 transcripts, TCRG end-stage rearrangement and predominant TCRD deletion, in keeping with cases arrested during beta-selection. This category included 90% of pediatric cases but only 56% of adults. 85% corresponded to thymic disease and bone marrow involvement was rare. In contrast, TCRB VDJ - cases were CD1a, CD4, and CD8 negative, with variable expression of CD2 50%, CD5 60%, CD34 40% and CD117 10% and low or absent pTa and RAG1. They include 2 cases with complete TCRD and TCRG rearrangement, but the majority either demonstrate no clonal TCRG or TCRD rearrangement (n=8) or only incomplete TCRD rearrangement (n=4). As such, they correspond to immature cells which could include T lymphoid, NK and/or dendritic precursors. This category was frequent in adults (44%) but rare in children (10%) and was associated with lymphnode disease (75%) and frequent bone marrow involvement (50%). Oncogenic transcripts were analysed in 8 children and 26 adults. TLX1 was over-expressed in 3 adult TCRB VDJ+ cases. HOXA5 and HOXA9 were over-expressed in 7 cases, including the 2 CALM-AF10 cases, 4 TCRB VDJ+ cases and the single case with NUP214-ABL. Only 1 case had LMO1 and TAL1 over expression and none were SIL-TAL1 or TLX3 positive. LMO2 and LYL1 expression was restricted to TCRB VDJ-T-LL. As for adult T-ALLs, initial response to induction was better in adult TCRB VDJ+ T-LL.

In conclusion, pediatric T-LL is a predominantly thymic disease arrested during beta-selection but with different oncogenic profiles to T-ALLs arrested at the same stage. Adult T-LL includes approximately 55% of cases with similar characteristics, with the rest corresponding to immature tumors of lymphnode origin, frequent partial bone marrow involvement and a probable inferior response to ALL type induction. TCRB clonality detection represents a simple method which will allow rapid distinction of these T-LL categories and prospective evaluation of their response in therapeutic trials. Transmission of appropriate diagnostic material to specialised diagnostic plateforms will allow better understanding of T-LL, particularly identification of the lineage potential of TCRB VDJ negative cases.