Characterization of childhood precursor T-lymphoblastic lymphoma by immunophenotyping and fluorescent in situ hybridization: A report from the Children's Oncology Group

Department of Pathology, University of Utah Health Sciences Center, ARUP Laboratories, Salt Lake City, Utah, USA.
Pediatric Blood & Cancer (Impact Factor: 2.39). 10/2008; 51(4):489-94. DOI: 10.1002/pbc.21666
Source: PubMed


T-lymphoblastic lymphoma (T-LBL) accounts for 25-30% of childhood non-Hodgkin's lymphoma and is closely related to T-lymphoblastic leukemia (T-ALL). Recently, we demonstrated distinct differences in gene expression between childhood T-LBL and T-ALL, but molecular pathogenesis and relevant protein expression patterns in T-LBL remain poorly understood.
Children with T-LBL with disseminated disease were registered and treated on COG protocol 5971. Paraffin-embedded tumor tissue was obtained at diagnosis for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) studies. We determined the pattern and intensity of staining for c-Myc, Skp2, Mib-1, p53, TCL-1, bcl-2, and bcl-6 proteins by IHC and c-Myc, p53, bcl-2, bcl-6, and TCR alpha/delta molecular alterations by FISH in 22 pediatric T-LBL cases.
The majority of T-LBL samples expressed Mib-1 (59%) and c-Myc (77%) proteins in greater than 50% of the cells, but Skp2 (14%), p53 (14%), and bcl-2 (23%) expression was less common. FISH studies demonstrated 18% gains and 10% losses in c-Myc, 16% gains in p53, 12% gains and 6% losses in bcl-2, and 6% gains and 19% losses in bcl-6 with little direct correlation between the IHC and FISH studies.
Childhood T-LBL is a highly proliferative tumor associated with enhanced expression of c-Myc protein, but without detectable c-Myc molecular alterations. FISH studies did not identify consistent etiologies of molecular dysregulation, and future studies with other molecular approaches may be required to elucidate the molecular pathogenesis of childhood T-LBL.

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    • "Besides the immunophenotypic subclassification of the Tcell maturation status, immunohistochemical staining can be used for studies on protein expression of genes that are implicated in leukaemia/lymphoma pathogenesis. A recent study reported immunophenotypic characteristics of 22 cases of paediatric T-LBL, using immunohistochemical staining and fluorescence in situ hybridization (FISH) (Smock et al, 2008 "
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    ABSTRACT: There is ongoing discussion on whether paediatric acute T-cell lymphoblastic leukaemia (T-ALL) and paediatric lymphoblastic T-cell lymphoma (T-LBL) are two distinct entities or whether they represent two variant manifestations of one and the same disease and the distinction is arbitrary. Both show overlapping clinical, morphological and immunophenotypic features. Many clinical trials use the amount of blast infiltration of the bone marrow as the sole criterion to distinguish between T-ALL and T-LBL. The current World Health Organization classification designates both malignancies as T lymphoblastic leukaemia/lymphoma. However, subtle immunophenotypic, molecular and cytogenetic differences suggest that T-ALL and T-LBL might be biologically different in certain aspects. The current review summarizes and discusses the recent advances and understanding of the molecular profile of paediatric T-ALL and T-LBL.
    British Journal of Haematology 11/2009; 149(5):653-68. DOI:10.1111/j.1365-2141.2009.08006.x · 4.71 Impact Factor
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    ABSTRACT: PURPOSE Disease dissemination to the bone marrow is detected at diagnosis in approximately 15% of children with T-cell lymphoblastic lymphoma (T-LL). It is unclear whether the remaining patients have submicroscopic systemic disease and, if so, what is the clinical significance of this finding. PATIENTS AND METHODS Using a flow cytometric method that can detect one T-LL cell among 10,000 normal cells, we examined bone marrow and peripheral-blood samples collected from 99 children with T-LL at diagnosis, as well as blood samples collected from 42 patients during treatment. Results In 71 (71.7%) of the 99 marrow samples obtained at diagnosis, T-LL cells represented 0.01% to 31.6% (median, 0.22%) of mononuclear cells; 57 of the 71 T-LL-positive samples were from patients with stage II/III disease. Results of studies in bilateral marrow aspirates were highly concordant. Two-year event-free survival (EFS) was 68.1% +/- 11.1% (SE) for patients with > or = 1% T-LL cells in bone marrow versus 90.7% +/- 4.4% for those with lower levels of marrow involvement (P = .031); EFS for patients with > or = 5% lymphoblasts was 51.9% +/- 18.0% (P = .009). T-LL cells were as prevalent in blood as in marrow; monitoring residual T-LL cells in blood during remission induction therapy identified patients with slower disease clearance. CONCLUSION More than two thirds of children with T-LL have disseminated disease at diagnosis, a proportion much higher than previously demonstrated. Measurements of disease dissemination at diagnosis might provide useful prognostic information, which can be further refined by monitoring response to therapy through blood testing.
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    ABSTRACT: Although deletions of cell cycle regulatory gene loci have long been reported in various malignancies, little is known regarding their relevance in pediatric T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (TALL). The current study focused on loss of heterozygosity (LOH) analyses of the CDKN2A/B (chromosome 9p), ATM (chromosome 11q) and p53 (chromosome 17p) gene loci. Frequencies of LOH were compared in 113 pediatric T-LBL and 125 T-ALL who were treated uniformly according to ALL-BFM strategies. Furthermore, LOH findings were correlated with clinical characteristics and tested for their prognostic relevance. LOH at 9p was detected in 47% of T-LBL and 51% of T-ALL, and was associated with male gender in both. In T-ALL, LOH at 9p was associated with favorable initial treatment response. A tendency for favorable event-free-survival was observed in LOH 9p positive T-LBL. The frequency of LOH at chromosomes 11q and 17p was 5% or less for both diseases.
    Haematologica 08/2009; 95(1):158-62. DOI:10.3324/haematol.2009.007526 · 5.81 Impact Factor
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