Pediatric T-Cell Lymphoblastic Leukemia and T-Cell Lymphoblastic Lymphoma: One and the Same or Two Different Diseases?.
Authors: Krieger David , Moericke Anja , Klapper Wolfram , Greene Franziska , Zimmermann Martin , Schrappe Martin , Reiter Alfred , Burkhardt Birgit 
Published: April 2020

Background/Objectives: Precursor T lymphoblastic neoplasms in children and adolescents are currently classified as either acute lymphoblastic T-cell leukemia (T-ALL) in case of ≥25% bone marrow involvement or lymphoblastic T-cell lymphoma (T-LBL) in case of &lt;25% bone marrow involvement. This distinction is considered to be largely arbitrary because of overlapping biological and clinical features. However, comparative studies of smaller patient series reported differences of immunophenotypic and molecular genetic parameters, suggesting that T-ALL and T-LBL might indeed be biologically different. While deletions of certain chromosomal regions have long been identified in pediatric T-ALL, for T-LBL molecular or cytogenetic data are scarce.

Design/Methods: The current study focused on the frequency, the association with clinical characteristics and the prognostic impact of selected chromosomal deletions, comparing 119 T-LBL patients (pts) with 125 T-ALL pts. T-LBL and T-ALL pts were registered in the NHL-BFM or ALL-BFM study center respectively. Both groups were treated according to ALL-BFM type treatment strategies. The molecular genetic analyses focused on chromosomal regions, harboring genes of functional relevance. Deletions were examined through loss-of-heterozygosity (LOH) analyses of 46 microsatellite markers. The following regions were analyzed: Chromosome 6q (25 markers), 7q (4 markers), 9p (5 markers), 11q (5 markers), 12p (6 markers) and p53 (1 marker). Samples of tumor and germline DNA were amplified by PCR, followed by fragment-length analysis with a genetic analyzer.

Results: In 119 T-LBL pts a total of 4,780 markers and in 125 T-ALL pts a total of 5,730 markers were analyzed successfully. The frequency of LOH is depicted in table 1.

Frequency of LOH in T-ALL and T-LBL patients T-LBL (n LOH + pts / n total pts) T-ALL (n LOH + pts / n total pts) p-value (Fisher) LOH at 6q 25 / 118 21% 15 / 125 12% 0.059 LOH at 7q 7 / 119 6% 2 / 124 2% 0.097 LOH at 9p 57 / 116 49% 63 / 125 50% 0.898 LOH at 11q 11 / 116 9% 3 / 125 2% 0.026 LOH at 12p 13 / 119 11% 9 / 125 7% 0.374 LOH at p53 4 / 76 5% 1 / 108 1% 0.161

Regarding clinical characteristics, LOH at 9p was associated with male gender in T-ALL and T-LBL. However, LOH at 9p was associated with elevated LDH level in T-ALL, but not in T-LBL. LOH at 12p was associated with female gender and mediastinal mass in T-ALL. In T-LBL, the 11 positive cases with LOH 12p showed an uncommon distribution of disease stages with more frequent stage II and stage IV disease. Regarding the prognostic impact, LOH at 6q was associated with an increased relapse rate in T-LBL but not in T-ALL. Interestingly, 2 of 3 T-ALL pts with LOH at 11q suffered from relapse compared to 0 out of 11 LOH 11q positive T-LBL pts. LOH at all other loci was not associated with a significant change in the risk of relapse.

Conclusions: Chromosomal deletions found in pediatric T-ALL were also detected in pediatric T-LBL. However, the frequency, the association with clinical characteristics and the prognostic impact of these deletions differ between pediatric T-LBL and T-ALL. These results might be a new indicator that there are indeed differences between pediatric T-LBL and T-ALL.