Genetic Testing in the Diagnosis and Biology of Acute Leukemia

2017 Society for Hematopathology/European Association for Haematopathology Workshop Report

Marian H. Harris, MD, PhD; David R. Czuchlewski, MD; Daniel A. Arber, MD; Magdalena Czader, MD, PhD


Am J Clin Pathol. 2019;152(3):322-346. 

In This Article

T Lymphoblastic Leukemia/Lymphoma

T lymphoblastic leukemia (T-ALL) is a malignancy of T-cell precursors that comprises 10% to 15% of pediatric ALL and 20% to 25% of adult ALL. NOTCH1 pathway activation is present in most cases and commonly occurs via NOTCH1 mutations but may also occur via FBXW7 mutations (which impede degradation of activated NOTCH1) or, rarely, via NOTCH1 rearrangement. NOTCH1 and FBXW7 alterations may co-occur. Rearrangements between the regulatory region of a T-cell receptor locus and an oncogenic transcription factor are also common, typically leading to deregulated expression of the transcription factor (eg, TAL1 or TLX1), as are rearrangements resulting in chimeric fusions (such as fusions of MLLT10, KMT2A, ABL1, or NUP98 with a variety of different gene partners).[46] The only subgroup of T-ALL recognized by the WHO classification (as a provisional category) is ETP-ALL.[1] ETP-ALL is defined immunophenotypically as showing positivity for CD3 (usually cytoplasmic) and CD7, negativity for CD8 and CD1a, coexpression of myeloid/stem cell markers, and expression of CD5 on less than 75% of blasts. Although characteristic genetic changes have been described, including less frequent alteration of NOTCH1 and CDKN2A and a higher frequency of mutations affecting signaling, transcriptional, and epigenetic pathways compared to other T-ALL,[46–48] these genetic patterns are not diagnostic. The CAP/ASH guidelines and the NCCN guidelines both recommend conventional karyotype in T-ALL; the CAP/ASH guidelines also recommend testing for mutations in NOTCH1 and FBXW7.[2,49] Only four T-ALL cases were submitted (cases 165, 189, 232, and 259; Table 3 except case 232 in Table 4). Karyotype was attempted in two cases but only successful in one. Two cases were sequenced and showed IL7R insertion mutations, which are almost exclusively seen in lymphoid malignancies, helping to support the diagnosis of T-ALL. Case 165 described a 23-year-old HIV-positive man with a diagnosis of T-ALL/LBL and a subsequent blastic undifferentiated neoplasm, which showed no expression of lineage specific markers despite extensive immunophenotyping. Sequencing was not performed in this case.