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T Cell Receptor Genotyping and HOXA/TLX1 Expression Define Three T Lymphoblastic Lymphoma Subsets which Might Affect Clinical Outcome

Authors' Affiliations: ¹ INSERM EMI0210, and Université Paris V, Hopital Necker Enfants-Malades, ² Department of Pathology and ³ Laboratory of Hematology, Hopital Necker Enfants-Malades, Assistance Publique-Hopitaux de Paris (AP-HP), ⁴ Department of Pathology, Hopital Henri Mondor, AP-HP, ⁵ Department of Hematology, Hopital Saint-Louis, AP-HP, ⁶ Department of Pathology, Hotel Dieu, AP-HP, Paris, France, ⁷ Department of Pathology, Centre Leon Berard, ⁸ Department of Pediatric Hematology, Hopital Debrousse, Hospices Civils de Lyon, Lyon, France, ⁹ Department of Hematology, Centre Henri Becquerel, Rouen, France, and ¹⁰ Department of Pathology, Centre Hospitalier Universitaire de Limoges, Limoges, France

Requests for reprints: Elizabeth Macintyre, Laboratoire d'Hématologie, Tour Pasteur, Hôpital Necker, 149-161, rue de Sèvres, 75743 Paris cedex 15, France. Phone: 33-14449-4947; Fax: 33-14438-1745; E-mail: elizabeth.macintyre{at}nck.ap-hop-paris.fr.

Purpose: T lymphoblastic lymphomas (T-LBL) are rare disorders of immature T cells which predominantly involve the mediastinum. Their oncogenic pathways and prognostic variables are not clear.

Experimental Design: We undertook a retrospective study of 41 cytoplasmic CD3+ T-LBL (nine cases aged <16 years) by assessing stage of maturation arrest based on T cell receptor (TCR) immunogenotyping, immunohistochemistry, and quantification of the oncogenes thought to be important in immature T cell malignancies.

Results: Application of a TCR-based immunogenetic classification allowed the identification of three subcategories: 11 immature IM0/D-LBL showed no TCR or only incomplete TCRD DJ rearrangement and corresponded to cytoplasmic CD3+ precursors of uncertain lineage. Sixteen mature TCRD^del-LBL showed biallelic TCRD deletion and both TCRG and TCRB rearrangement, consistent with TCRβ lineage restriction. Fourteen intermediate LBL (Int-LBL) showed complete TCRD VDJ and TCRG VJ rearrangement, with TCRB VDJ rearrangement in the majority. All Int-LBL expressed HOX11/TLX1 or HOXA9 transcripts and a proportion of the latter were associated with CALM-AF10 or NUP214-ABL fusion transcripts. IM0/D-LBL were restricted to adults with extrathymic disease and bone marrow involvement, whereas Int-LBL and TCRD^del-LBL were found in children and adults with predominantly thymic disease. In adults, the Int-LBL subgroup was associated with a significantly superior clinical outcome. This subgroup can be identified either by TCR immunogenotyping or HOXA9/TLX1 transcript quantification.

Conclusion: Application of this molecular classification will allow the prospective evaluation of prognostic effects within pediatric and adult protocols.