The most common childhood malignancy is acute lymphoblastic leukemia (ALL), representing approximately one-third of all newly diagnosed pediatric malignancies. Two types of ALL exist, those involving B cells and those involving T-cells, with T-cell ALL comprising 10-25% of all cases.

T-cells mature in the thymus orchestrate cellular immunity, and are integral to the process of humoral immunity provided by B-cells. Early thymic progenitors, or lymphoblasts, enter the thymus, and in their journey through this organ differentiate by the process of somatic rearrangement of T-cell receptor (TCR) genes. The completely differentiated T-cell must be both functional and self-tolerant, a stringent requirement which results in an approximately 95% attrition rate of mature T-cells. The approximately 5% that actually leave the thymus circulate in the blood as well as through lymphatic and non-lymphatic organs [Karrman and Johansson, 2017]. T-ALL is, therefore, a neoplasm of these lymphoblasts committed to the T-cell lineage.

Because of the relatively low incidence of T-ALL compared with B-ALL, there is more data specifically regarding the etiology of B-ALL; however, the two diseases may share causative mechanisms. Both environmental exposure and genetic predisposition have been cited as possible etiologies for ALL, with exposure to ionizing radiation considered a known risk factor. The inheritance of both rare high penetrance, and more common low penetrance alleles, have been suggested by several studies, with inherited polymorphisms of CDKN2A the only confirmed variant directly attributable to an increased risk of developing T-ALL. In addition, genetic predisposition has also been demonstrated in a few studies where families have shown a high concordance of T-ALL in siblings [Karrman and Johansson, 2017].
It is the progressive accumulation of both genetic and epigenetic changes involving the immature thymocyte within the thymus that leads to T-ALL. Approximately half of all patients with T-ALL present with chromosome rearrangements that involve T-cell receptor genes, most commonly T-cell receptors α and δ (TRA and TRD, respectively) at chromosome band 14q11, T-cell receptor β (TRB) at chromosome band 7q34, or T-cell receptor γ (TRG) at 7p14.1. Unlike non-malignant conditions that give rise to a polyclonal T-cell response, T-cell ALL arises from a single cell that gives rise to a clone with an identical T-cell receptor gene rearrangement. These rearrangements will juxtapose one of these T-cell receptor genes with many critical partner genes, many of which code for transcription factors. This results in dysregulation of transcription of the partner gene, which is the main driver in leukemogenesis. Some of the most common partner genes include HOX11 (TLX1) at 10q24, HOX11L2 (TLX3) at 5q35, MYC at 8q24.1, TCL1 at 14q32, TAL1 at 1p32, LMO1 at 11p15, LMO2 at 11p13, and LYL1 at 19p13. As many of these rearrangements are submicroscopic, they cannot routinely be detected by conventional cytogenetic analysis, but require fluorescence in situ hybridization (FISH) to confirm the diagnosis. Approximately 20% of cases will also demonstrate simultaneous rearrangement of IGH@ [Borowitz and Chan, 2008].
DNA sequence mutations and copy number variants are also identified in T-ALL and are believed to be significant contributors to leukemogenesis. These mutations are found in genes involved in the JAK-STAT and Ras/PI3K/AKT pathways, in epigenetic regulation, in mRNA maturation and ribosome activity, in modifying histone methylation or acetylation, and that function as regulators of transcription. In fact, mutations in epigenetic regulators are found in over 50% of pediatric T-ALL cases, making this a common mechanism of tumorigenesis. Activating mutations of NOTCH1 (occurring in at least 60% of T-ALL cases) and loss-of-function mutations in FBXW7 are also commonly found in T-ALL and result in inhibition of ubiquitin-mediated degradation of the activated form of NOTCH1 [Iacobucci and Mullighan, 2017; Karrman and Johansson, 2017].

Approximately 6000 new cases of ALL are diagnosed each year in the United States. T-ALL can occur in children or adults, but is more common in the pediatric population and more often diagnosed in adolescents than in young children, with a median age of onset of 9 years, compared with the more common precursor B-cell ALL which has an incidence peak between 2 and 5 years. In addition, there is a marked male predominance, with boys having a threefold-increased risk of developing T-ALL compared with females. It is unclear why T-ALL is primarily a disease of older children and why males are more preferentially affected compared with B-ALL [Karrman and Johansson, 2017].

Both T-ALL and T-cell lymphoblastic lymphoma (T-LBL) are aggressive and highly heterogenous diseases which originate from genetic and epigenetic alterations in immature thymocytes during the process of differentiation within the thymus. T-ALL and T-LBL, which demonstrate overlapping clinical, morphological and immunophenotypic features, have been considered different manifestions of the same disease, with the only difference being the site of presentation. T-ALL patients present with extensive bone marrow involvement and lymphoblasts in peripheral circulation, a mediastinal mass in two-thirds of patients, splenomegaly, adenopathy, and central nervous system involvement. T-LBL is primarily confined to a mediastinal mass lesion with minimal or no bone marrow involvement. [Burkhardt 2010; Karrman and Johansson, 2017]. However, subtle immunophenotypic, molecular and cytogenetic differences suggest that T-ALL and T-LBL may, in fact, be biologically distinct diseases [Burkhardt 2010; Basso et al, 2011].
T-ALL can present acutely or with symptoms that develop and progress over several months. Proliferation of the malignant clone in different tissues accounts for the common clinical features of T-ALL. Expansion of the clone within the bone marrow results in a high leukocyte count and a concurrent suppression of normal hematopoiesis, resulting in deficiency of normal peripheral blood cells, especially thrombocytes. Symptoms include fever, joint and bone pain, recurrent infection, lethergy, paleness, mucosal bleeding, and hepatosplenomegaly. CNS involvement results in neurological symptoms including headache, visual impairment, and nausea. The mediastinal mass seen in approximately 50-60% of T-ALL patients can cause superior vena cava syndrome. The mediastinal mass(s) found in T-LBL predomininately involve the anterior mediastinum and cause progressive dyspnea with cough, edema, and elevated jugular venous pressure. While the clinical manifestations are somewhat different, the only true distinguishing feature between T-ALL and T-LBL is the blast count in bone marrow (>25% blasts in T-ALL). [Burkhardt, 2010]

The lymphoblasts in B-ALL and T-ALL are morphologically indistinguishable from one another, necessitating the use of immunophenotyping for lineage determination. ALL blasts are generally of intermediate size (up to twice the size of a small lymphocyte) with a high nuclear/cytoplasmic ratio, although there can be variation in size range. The blasts demonstrate scant, basophilic cytoplasm with homogenous and somewhat condensed chromatin. Nucleoli may or may not be present depending on the size of the blast, as might cytoplasmic vacuoles. When the blasts resemble more mature lymphocytes, immunophenotyping is required to distinguish T-ALL from a mature (peripheral) T-cell leukemia [Borowitz and Chan, 2008; Onciu M, 2007].
As mentioned, immunophenotyping by immunohistochemistry and/or flow cytometry is critical in cases of ALL to determine the cell lineage (B-cell vs. T-cell). All T-cell ALLs express CD45 and cytoplasmic CD3 (CD3 may also be weakly expressed on the cell surface), with CD3 being T-cell lineage specific and thus an important maker for lineage differentiation. Other T-cell antigens consistently expressed include CD2, CD5, and CD7. The DNA polymerase terminal deoxynucleotidyl transferase (TdT) is expressed in 80-90% of T-ALL cases. In addition, variable expression of CD1, CD4, CD8, CD10, and CD56 is observed. Lineage-inappropriate expression of myeloid markers including CD11b, CD13, CD33, and CD66c are also observed; however, their expression is of no prognostic significance and do not necessarily warrant a diagnosis of biphenotypic leukemia [Onciu M, 2007; Karrman and Johansson, 2017].
Because the expression of CDs change with the maturation stage of thymocytes, the array of CD markers in a case can indicate the stage at which the differentiation block occurred. The stages of differentiation include: 1) pro-T (cCD3+, CD7+, CD2-, CD1a-, CD34+/-); 2) pre-T (cCD3+, CD7+, CD2+, CD1a-, CD34+/-); 3) cortical T (cCD3+, CD7+, CD2+, CD1a+, CD34-); and 4) medullary T (cCD3+, CD7+, CD2+, CD1a-, CD34-, surface CD3+) [Borowitz and Chan, 2008]. Cases of pro- and pre T-ALL tend to have a more inferior outcome compared with those designated as cortical or medullary T-ALL. The recently delineated category of T-ALL known as early T-cell precursor ALL (ETP-ALL) has a distinct immunophenotype. This T-ALL demonstrates an immature immunophenotype, expresses myeloid and/or stem cell markers, and has a poor outcome; however, recent studies suggest intensive treatment can overcome the poor prognostic outcome in some patients [Belver and Ferrando, 2016; Karrman and Johansson, 2017].

Patients with T-cell ALL generally present with more high-risk features than do those with B-ALL. These features include an increased resistance to chemotherapy, a tendency for earlier relapse, and CNS involvement. Therefore, most patients are treated aggressively, including intrathecal chemotherapy and CNS radiation therapy. The outcome of children with T-ALL has improved with intensification of multimodal therapy. Chemotherapy regimens in children with T-ALL include initial induction therapy for 4-6 weeks followed by intensive combination therapy for 6-8 months and low-intensity anti-metabolite-based therapy for 18-30 months. Induction therapy includes vincristine, a glucocorticoid such as dexamethasone, L-asparaginase, and possibly an anthracycline such as daunorubicin [Hunger and Mullighan, 2015].
Allogeneic hematopoietic stem cell transplantation has been found to be an effective treatment for high-risk T-ALL patients; however, relapse is not uncommon in such cases, reducing its curative potential. Continuous monitoring for minimal residual disease following transplantation, using various molecular methods including qPCR to evaluate for fusion transcripts such as SIL/TAL1, is critical so that immediate intervention can be provided at an early stage of relapse [Zhao et al, 2017].

The improvement in outcome of children with T-ALL continues to lag behind its B-cell counterpart. With risk-stratified consolidated chemotherapy, 5-year event free survival for B-ALL stands at 80% and overall survival at 90%. However, 5-year event free survival and overall survival for T-ALL is just over 70% and 80%, respectively. Patients with T-ALL have more induction failures and extramedullary relapses than those with B-ALL. Relapsed T-ALL occurs in up to 25% of children and is associated with a much poorer prognosis (30-50% survival). Therefore, monitoring for minimal residual disease (MRD), usually by qPCR analysis of TCR genes is critical to evaluate the effectiveness of treatment [Pui CH et al, 2015; Karrman and Johansson, 2017]. If a child continues to have a high level of MRD at the end of induction, the risk of relapse is high [Chu et al, 2017]. Recent genomic studies have begun to uncover the basis for relapse in this disease, which appears to involve both clonal evolution and selection of genetic variants that drive resistence. One such variant involves mutation in the cytosolic 5-nucleotidase II ( NT5C2) gene which are found in 20% of patients with relapsed T-ALL [Tzoneva et al, 2013]. In addition, the TFDP3 gene has been found to confer chemoresistance in children with T-ALL with MRD [Chu et al, 2017].

Routine karyotyping in T-ALL cases identifies a structural chromosome rearrangement, primarily translocations and inversions, in 55-75% of patients; however, utilization of FISH and/or molecular technologies such as single nucleotide polymorphism (SNP) array can substantially increase diagnostic yield. The karyotypes in pediatric T-ALL are generally near-diploid and are rarely complex. The most common chromosome abnormalities identified in T-ALL involve rearrangement of one of the T-cell receptor (TCR) genes, considered pathognomonic for the disease. The T-cell receptor genes that most commonly undergo recombination are TRD and TRB, with TRA seldom involved and TRG rarely rearranged. The rearrangements affecting TCR genes are initiated by the normal process of TCR recombination, with illegitimate recombination occurring when the cellular machinery fails to correctly repair the requisite double-strand breaks (DSBs) induced by recombination-activating RAG proteins [Karrman and Johannson, 2017].
Rearrangements which place a gene with transforming capacity next to one of the TCR genes enhancers or promoters can result in transcriptional dysregulation of the gene, leading to altered differentiation and growth. There are over 30 genes that are known to recombine illegitimately with TCR genes in T-cell ALL. These genes and their associated proteins function primarily as transcription factors (oncogenes or tumor suppressors), to regulate the cell cycle, as epigenetic regulators, as ribosomal proteins, and as signal transducers.
A thorough review of cytogenetic aberrations in T-cell ALL has been published in the ATLAS previously by Susana Raimondi [Raimondi, 2007]. What follows is a summary of the major cytogenetic aberrations identified in T-cell ALL. The reader is encouraged to access "T-lineage acute lymphoblastic leukemia (T-ALL)" in the ATLAS (Atlas ID 1374) for further discussion of these and other abnormalities in T-ALL.
Unless otherwise noted, the information is abstracted from Raimondi, 2007 and Karrman and Johansson, 2015: