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Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma

Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma
Authors:
Anjali S Advani, MD
Jon C Aster, MD, PhD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Oct 03, 2022.

INTRODUCTION — Lymphoblastic neoplasms, which may present as leukemia or lymphoma, are referred to as acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) because the World Health Organization classification system for hematologic malignancies does not distinguish between clinical presentations as leukemia or lymphoma [1,2]. An individual case is defined as lymphoma (LBL) if there is a mass lesion (in the mediastinum or elsewhere) and <20 percent blasts in the bone marrow, while cases with ≥20 percent bone marrow blasts (with or without a mass lesion) is described as ALL; nevertheless, either presentation can evolve into the other [3].

ALL/LBL is divided into two general categories based upon lineage (see "Classification of hematopoietic neoplasms") [1,2]:

Precursor B cell ALL/LBL

Precursor T cell ALL/LBL

Prognosis and treatment differ between neoplasms of B and T cell lineage.

The pathobiology, diagnosis, and clinical presentation of precursor T ALL/LBL is discussed in this topic.

Treatment of T cell ALL/LBL is discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents" and "Treatment and prognosis of adult T cell leukemia-lymphoma".)

Diagnosis of precursor B cell ALL/LBL is discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

CELL OF ORIGIN — Precursor T lymphoblastic leukemia/lymphoblastic lymphoma (T cell ALL/LBL) is postulated to arise from precursor T lymphoblasts at varying stages of differentiation. As with other forms of acute leukemia, in experimental systems only a small subset of tumor cells appears to be able to establish disease in immunodeficient mice, suggesting that the tumor is maintained by a small number of leukemia initiating cells (so-called leukemia stem cells). Uncertainty remains regarding the precise identity of these cells, which may lie at the root of T cell ALL/LBL and therefore represent key cells to target if patients are to be cured [4].

EPIDEMIOLOGY — Precursor T cell LBL/ALL occurs most frequently in late childhood, adolescence, and young adulthood, with a 2:1 male predominance; it comprises 15 and 25 percent of childhood and adult ALL/LBL, respectively, and 2 percent of adult non-Hodgkin lymphoma [3,5-7]. The incidence in the United States is approximately three cases per million persons per year and does not vary by ethnicity [7].

CLINICAL PRESENTATION — Patients are usually males in their teens to early twenties who present with lymphadenopathy in cervical, supraclavicular, and axillary regions (50 percent), or with a mediastinal mass (50 to 75 percent) [8,9]. In most patients the mediastinal mass is anterior, bulky, and associated with pleural effusions. These masses can produce such complications as superior vena cava syndrome, tracheal obstruction, and pericardial effusions (with or without tamponade). The disease tempo is variable with some patients presenting with symptoms progressing slowly over weeks to months and others more acutely. (See "Malignancy-related superior vena cava syndrome".)

Less commonly, patients present with extranodal disease (eg, skin, testicular, or bony involvement). Abdominal involvement is very unusual; when it does occur it is primarily in the liver and spleen.

More than 80 percent of patients present with stage III or stage IV disease and almost 50 percent have B symptoms; in the majority, serum lactate dehydrogenase (LDH) levels are elevated. Although the bone marrow is frequently uninvolved at presentation, approximately 60 percent of patients develop bone marrow infiltration and a subsequent leukemic phase indistinguishable from T cell ALL [10].

Evaluation of the spinal fluid is essential to rule out central nervous system (CNS) involvement, which is frequently seen. Patients with bone marrow involvement have a particularly high incidence of CNS infiltration, which typically takes the form of leptomeningeal disease. Parenchymal involvement of the brain may occur in both T-ALL and B-ALL, but is much less common.

PATHOLOGIC FEATURES

Morphology — On peripheral blood smears, lymphoblasts vary from small cells with scant cytoplasm, condensed nuclear chromatin, and indistinct nucleoli to larger cells with moderate amounts of cytoplasm, dispersed chromatin, and multiple nucleoli. A few azurophilic cytoplasmic granules may be present. Auer rods are never seen.

In tissue sections, the tumor cells are small to medium-sized, with scant cytoplasm, round, oval, or convoluted nuclei, fine chromatin and indistinct or small nucleoli (picture 1 and picture 2 and picture 3). Occasional cases have larger cells. Precursor T cell LBL/ALL is morphologically indistinguishable from precursor B cell ALL/LBL.

Immunophenotype and histochemistry — As in B cell ALL/LBL, evaluation often includes both histochemistry and flow cytometry. On histochemistry, the blasts often show "chunky" positivity on periodic acid Schiff (PAS) staining, are variably positive for nonspecific esterase and Sudan black B, and are negative for myeloperoxidase.

On flow cytometry, the lymphoblasts are typically positive for CD7 and either surface or cytoplasmic CD3, and variably express CD2, CD5, CD1a, CD4 and/or CD8 (figure 1). A subset of tumors is positive for CD10 (CALLA). Only surface CD3 is entirely lineage-specific, and a panel of markers should be used to confirm the diagnosis. The stage of T cell differentiation can then be determined by evaluation of a constellation of antigens (earliest to latest) [11]:

Early or pro-T – CD2, CD5, CD7, CD38 and cytoplasmic CD3 (30 percent)

Common thymocyte – CD1a, sCD3, CD4/CD8 double positive (50 percent)

Late thymocyte – CD4 or CD8 single positive (20 percent)

There is some correlation with presentation and differentiation stage (cases with bone marrow and blood presentation in general are arrested at earlier differentiation stages than cases with thymic presentation [12,13]); however, there is significant overlap [14]. Historically, presentation with the most immature form of T ALL/LBL, referred to as early T cell progenitor (ETP) ALL/LBL, has been associated with worse outcomes than T ALL/LBL with more mature immunophenotypes in both children [15-17] and adults [18,19]. However, newer treatment regimens and risk stratification by measurable residual disease (MRD) may be improving outcomes in ETP ALL/LBL [20].  

Approximately one-half of cases of T cell ALL/LBL express the homing receptor/cell adhesion molecule CD44. Expression of CD44 correlates with maturation, as CD4-negative/CD8-negative tumors are CD44+ whereas CD4+/CD8+ tumors tend to be CD44-negative. CD10, on the other hand, correlates with lymphomatous presentation, as approximately 40 percent of T cell LBLs express CD10; by comparison, less than 10 percent of T cell ALLs are CD10+.

Rare cases of LBL express antigens present on NK cells (CD16, CD57).

Genetic features — Rearrangement of antigen receptor genes is variable in lymphoblastic neoplasms, and may not be lineage-specific; thus, precursor T cell neoplasms may have either or both T cell receptor (TCR) beta or gamma chain gene rearrangements and immunoglobulin heavy chain gene rearrangements [21]. As such, immunophenotyping is used to determine T cell or B cell lineage.

Chromosomal translocations involving either the TCR alpha and delta loci at chromosome 14q11 or the TCR beta and gamma loci at 7q34 are present in about one-third of the cases [22,23]; the partner genes are variable and include genes encoding transcription factors (eg, MYC (8q24), TAL1/SCL (1p32), LMO1 (11p15), LMO2 (11p13), and HOX11 (10q24)) and the gene for the cytoplasmic tyrosine kinase LCK (1p34). In an additional 25 percent, the TAL1 locus at 1p32 has deletions in the 5' regulatory region; together with translocations, rearrangements of TAL1 are the most common chromosomal aberration involving a proto-oncogene in T-ALL [24]. Deletions of 9p involving CDKN2A, a locus encoding two tumor suppressors, p16 (INK4a), a CDK4 inhibitor, and p14 (ARF), a protein that augments p53 function, are also seen in a high fraction of T-lymphoblastic neoplasms.

A rare t(7;9)(7q34;9q34.3) involving the NOTCH1 gene is found in less than 1 percent of T cell ALL/LBL. Much more common are oncogenic point mutations involving NOTCH1, which result in excessive activation of the NOTCH1 receptor [25]. Recognition of frequent NOTCH pathway activation in T cell ALL/LBL has led to attempts to treat refractory disease with NOTCH pathway inhibitors, specifically inhibitors of gamma-secretase, a protease that is required for Notch receptor activation, but only a minority of cases of relapsed/refractory NOTCH1-mutated tumors demonstrated complete responses [26-28].

One report found that 61 percent of pediatric patients had an abnormal karyotype, the most common abnormalities being del(6q) and 14q11 breakpoints. Other abnormalities included del(9p), trisomy 8, 11q23 breakpoints, 14q32 translocations, and 7q32-q36 breakpoints. In contrast to precursor B cell lymphoblastic leukemia/lymphoma, specific cytogenetic aberrations are not of prognostic significance in the patients with T cell ALL/LBL.

Integrated genomic analyses of T cell ALL/LBL have confirmed that genetic alterations involving genes encoding NOTCH1, T cell lineage transcription factors, and p16/p14 are the most common features of this disease, but many other mutations/copy number changes have been described involving genes encoding transcription factors, epigenetic regulators, and signaling molecules [29,30]. Certain mutations that are preferentially found at the time of relapse have been linked to therapy resistance, specifically gain of function mutations in NT5C2, which have been shown to generate resistance to 6-mercaptopurine and 6-thioguanine [31], and loss of function mutations of TP53, which are strongly associated with resistance to salvage therapy [32,33]. Other recent work has also identified changes in DNA methylation in T cell ALL/LBL as compared to normal thymocytes [34].

A more detailed discussion of chromosomal abnormalities in ALL/LBL is presented separately. (See "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)

EVALUATION AND DIAGNOSIS — T cell ALL/LBL is usually suspected in a child or adult with circulating lymphoblasts, painless lymphadenopathy, and/or mediastinal mass. It may also be suspected in the setting of unexplained cytopenias; fatigue, infections, easy or spontaneous bruising/bleeding; constitutional symptoms; bone pain; and/or hepatomegaly or splenomegaly. 

Evaluation — Evaluation should include a complete blood count (CBC) with differential count, examination of the peripheral smear, immunophenotype of peripheral blood or marrow, and bone marrow examination. In some cases, evaluation also includes an excisional or needle core biopsy of a mediastinal mass or lymph node.

We also evaluate acute leukemias by targeted exome sequencing on a next generation sequencing platform, which can provide useful prognostic information (eg, whether TP53 mutations are present).

Diagnosis — The diagnosis of T cell ALL/LBL is based on the results of a bone marrow biopsy, with or without biopsy of other involved tissues, such as the mediastinum. In addition to histological analysis, portions of the aspirated material or biopsy specimen should be sent for flow cytometry and cytogenetic evaluation.

Lymphoblasts are present in the blood, bone marrow, or tissue biopsy. Their morphology varies, but it is identical in T cell ALL/LBL and B cell ALL/LBL; in some instances, morphologic distinction from acute myeloid leukemia (AML) is difficult or impossible. Because antigen receptor gene rearrangements are not lineage-specific, immunophenotype plays a key role in the diagnosis of precursor T cell LBL/ALL.

The blasts can be distinguished from the myeloblasts of acute myeloid leukemia (AML) by their positivity for TdT (picture 4) and lack of staining for myeloperoxidase. T cell lineage is then identified by evaluation of a panel of T cell antigens, including CD3.

The term precursor T cell acute lymphoblastic leukemia (T ALL) is used if there are ≥20 percent bone marrow blasts, with or without a mass lesion. For cases with a mass lesion and <20 percent bone marrow involvement, the term precursor T cell lymphoblastic lymphoma (T LBL) is used.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for precursor T cell LBL/ALL includes other forms of lymphoma and leukemia. Most notably, T cell LBL/ALL is differentiated from B cell LBL/ALL by immunophenotypic analysis, which demonstrates the presence of T cell antigens and the absence of B cell antigens. In addition, precursor T and B cell LBL/ALL are differentiated from AML by their positivity for TdT and lack of staining for myeloperoxidase. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

Myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangement — Cases that are morphologically and immunophenotypically identical to T cell ALL/LBL that are associated with eosinophilia may represent T cell LBL with eosinophilia and a defining gene rearrangement, which is considered a distinct entity in the WHO classification of hematologic malignancies [35]. In addition to eosinophilia, marrow and peripheral blood examination often shows evidence of a myeloproliferative disorder. These neoplasms are associated with rearrangements of genes encoding tyrosine kinases, most often PDGFR-alpha or PDGFR-beta, and respond to tyrosine kinase inhibitors.

Indolent T-lymphoblastic proliferation — Indolent T-lymphoblastic proliferation is a nonmalignant entity that may mimic precursor T cell ALL/LBL histologically, but it is clinically indolent [1,36]. Most cases demonstrate infiltration of lymphoid tissue of the upper aerodigestive tract. Although infiltrating blasts are TdT positive, the cells are not clonal and have a developmentally normal, non-aberrant phenotype.

Lymphocyte rich thymoma — This tumor presents as a mediastinal mass that may mimic T cell ALL/LBL on imaging studies. It represents an epithelial neoplasm that continues to support thymocyte development. Histologically, the epithelial cells may be outnumbered by thymocytes, producing an appearance that superficially resembles T cell ALL/LBL. The distinction is made by performing immunohistochemistry for keratin, which highlights the underlying proliferation of epithelial cells; flow cytometry, which shows that unlike in T cell ALL/LBL, the thymocytes exhibit a range of differentiation; and in difficult cases, antigen receptor gene rearrangement studies, which show the proliferating thymocytes to be polyclonal. Notably, on rare occasions, T cell ALL/LBL and thymoma may co-exist within a single mediastinal mass [37].

PROGNOSTIC FACTORS — Prior to the development of aggressive therapies, T cell ALL/LBL was rapidly fatal. Currently, children with T cell ALL/LBL treated with such therapeutic regimens have outcomes similar to those of children with B-ALL/LBL. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)

Gene expression profiling and other studies have identified a number of genes associated with response to induction therapy and remission duration in T cell ALL [38]. The profiles in adults [39] and children [40] show some divergence, which might explain differences in outcomes of adults and children. On the other hand, adult chemotherapy regimens have not been as intensive as those used in children, and it remains possible that differences in therapy in adult and childhood T cell ALL/LBL (as well as B cell ALL/LBL) at least in part explain worse outcomes in adults.

Prognostic factors for T cell ALL/LBL were evaluated in 356 adult patients treated uniformly on the prospective trial UKALL XII/ECOG 2993, in which complete remission was observed in 94 percent and five-year overall survival was 48 percent. The following prognostic variables were described [41]:

Survival was significantly shorter for females than males (41 versus 50 percent) and for those >35 years of age (38 versus 52 percent).

Positivity of blasts for CD1a and lack of expression of CD13 were associated with significantly better survival. Complex cytogenetic abnormalities were associated with a significantly poorer five-year survival (19 versus 51 percent).

Patients with a matched sibling donor had significantly better five-year survival than those without such donors (61 versus 46 percent).

The outcome following relapse was dismal, with only 8 of the 123 (6.5 percent) relapsed patients surviving at a median of 5.2 years. Six of the eight survivors had undergone allogeneic transplantation. However, patients did not receive pediatric-inspired regimens and were not stratified by measurable residual disease (MRD).

In another study of 212 adults with T cell ALL/LBL enrolled on prospective trials, analysis for mutations in NOTCH1 and/or FBXW7 (N/F), KRAS, and PTEN was able to classify patients into prognostically "low-risk" and "high-risk" groups [42]. Approximately half of cases had a "low-risk" profile consisting of N/F mutations without K-RAS or PTEN mutations. When compared with all other patients, "low-risk" disease was associated with significantly longer event-free survival (hazard ratio [HR] 3.2; 95% CI 1.9-5.15) and overall survival (HR 3.2; 95% CI 1.9-5.6). MRD testing post-treatment at various time points is now considered standard in the follow-up and management of both B- and T-ALL and has been shown to be prognostic.

It also is increasingly appreciated that mutations in TP53 are found in 10 to 15 percent of T cell ALL/LBL, are particularly common in relapsed/refractory disease, and are associated with a dismal prognosis, particularly if they are associated with deletion of the other TP53 allele on chromosome 17q [43].

It is clear from these observations that disease relapse is a more common cause of death than failure to achieve complete remission. The pros and cons of hematopoietic cell transplantation for preventing relapse in ALL are discussed separately. (See "Hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Acute lymphoblastic leukemia (ALL) (The Basics)")

Beyond the Basics (see "Patient education: Acute lymphoblastic leukemia (ALL) treatment in adults (Beyond the Basics)")

SUMMARY

Precursor T-lymphoblastic leukemia/lymphoma (precursor T-LBL), also called precursor T cell acute lymphoblastic leukemia (precursor T cell ALL) is postulated to arise from precursor T lymphoblasts at varying stages of differentiation.

The term precursor T cell acute lymphoblastic leukemia (T-ALL) is used if there are >20 percent bone marrow blasts, with or without a mass lesion. For cases with a mass lesion and less than 20 percent bone marrow involvement, the term precursor T cell lymphoblastic lymphoma (T-LBL) is used. (See 'Introduction' above.)

Precursor T cell LBL/ALL occurs most frequently in late childhood, adolescence, and young adulthood, with a male predominance; it comprises 15 percent of childhood and 25 percent of adult ALL and 2 percent of adult non-Hodgkin lymphoma. (See 'Epidemiology' above.)

Peripheral blood smear, bone marrow biopsy, and tissue biopsy can demonstrate lymphoblasts with varying morphology. Precursor T-LBL/ALL is morphologically indistinguishable from precursor B-ALL/LBL. (See 'Morphology' above.)

Key diagnostic studies include histochemical stains, immunocytochemistry, and flow cytometry. These are required to differentiate among precursor T-ALL/LBL, precursor B-ALL/LBL, and other acute leukemias. (See 'Immunophenotype and histochemistry' above.)

A number of genetic abnormalities have been identified in patients with precursor T-ALL/LBL; at present, the most prognostically important of these are TP53 mutations. (See 'Genetic features' above and "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)

The diagnosis of precursor T-lymphoblastic leukemia/lymphoma is made based upon the results of a bone marrow biopsy with or without biopsy of other involved tissues, such as the mediastinum. (See 'Evaluation and diagnosis' above.)

Age at diagnosis is an important prognostic factor, but differences in outcome between children and adults may be related to differences in treatment rather than differences in disease biology.(See 'Prognostic factors' above.)

While not yet routine, all acute leukemias seen at our institution are subjected to analysis using a targeted next-generation sequencing platform that covers certain genes that are prognostically important in T-ALL/LBL, such as TP53.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Arnold S Freedman, MD, who contributed to earlier versions of this topic review.

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