A Practical Approach to the Diagnosis of Common Hematopoietic and Solid Tumors of Childhood
Case 8 -
Precursor T-Cell Lymphoblastic Lymphoma
D. Ashley Hill, M.D.
Mihaela Onciu M.D.
12-year-old boy with a large anterior mediastinal mass and
left cervical lymphadenopathy. A needle-biopsy of a left cervical lymph node was performed. Further
work-up showed normal bone marrow and peripheral blood.
Histologic sections showed a malignant lymphoid
neoplasm with diffuse growth pattern. The neoplastic cells were uniform and medium-sized, with regular
nuclear outlines, finely clumped chromatin and small inconspicuous to absent nucleoli. Frequent mitotic
figures were noted.
- Lymphoblastic lymphoma (precursor B-cell or precursor
- Other blastic neoplasms (myeloid sarcoma)
- Burkitt lymphoma
- Blastic variant of mantle cell lymphoma (In adults
Immunophenotypic Findings (Immunohistochemistry):
The lymphoma cells were weakly positive for CD45, CD3, CD1a, and Tdt, and were negative for CD79a.
Molecular / Cytogenetic Analysis:
Precursor T-cell lymphoblastic lymphoma/leukemia.
Precursor T-cell / Precursor B-cell Lymphoblastic Lymphoma / Leukemia
Precursor B-cell and T-cell tumors are neoplasms composed of
blasts (immature lymphoid cells) committed to the B-cell or T-cell lineage, respectively. They may
present with exclusive tissue infiltration (lymphoblastic lymphoma - LBL) or with tissue as well as
peripheral blood and bone marrow involvement (designated as acute lymphoblastic leukemia - ALL). The
arbitrary cut-off between LBL with marrow involvement and ALL has been established at 25% bone marrow
involvement by blasts. This cut-off is not based on biologic differences and is used at the current time
only as an arbitrary measure of tumor bulk (for staging purposes). While tumors diagnosed in the tissue
as precursor B-cell LBL are most often a manifestation of ALL, it is not unusual for precursor T-cell LBL
to be limited to peripheral involvement (most commonly anterior mediastinum) with no evidence of bone
ALL is the most common childhood malignancy and up to 75% of
ALL occur in children under 6 years of age. In Western countries the majority of cases (80-85%) have a
precursor B-cell immunophenotype, while only 15-20% are of T-cell lineage. The prevalence of T-cell ALL
is higher in Mediterranean countries, North Africa and the Middle East. Lymphoblastic lymphoma (i.e.
disease limited to the peripheral tissues with <25% bone marrow involvement) is predominantly of
T-cell lineage with a propensity towards anterior mediastinum as a primary site. Only ~10% of
lymphoblastic lymphomas are of B-cell lineage. The latter cases appear to have a somewhat distinct
clinico-pathologic spectrum (see below).
Children with precursor T-cell LBL/ALL often present
with signs of mediastinal compression ranging from shortness of breath and coughing to superior vena cava
syndrome, resulting from a bulky anterior mediastinal mass. Precursor B-cell LBL often involves the skin
(scalp), lymph nodes, soft tissues and bones of the head and neck, and appears to have a distinctively
better prognosis than B-cell ALL. The presenting features in ALL often reflect the degree of bone marrow
failure and extra-medullary involvement by the tumor. Thus, these patients may show signs and symptoms
of anemia, thrombocytpenia, neutropenia, or marked leukocytosis. In addition, ALL patients will commonly
present with fever, fatigue, bone or joint pain, abdominal pain, anorexia, and variable degrees of
hepatosplenomegaly and lymphadenopathy. Significantly increased LDH levels in this context may signify
extensive bone marrow necrosis. Following chemotherapy, LBL/ALL of any lineage may relapse at sites such
as cerebrospinal fluid/central nervous system, testes and ovaries.
Molecular Biology and Cytogenetics:
LBL/ALL are clonal proliferations of
precursor B-cells or T-cells "frozen" at an early stage of maturation. The genetic lesions associated
with malignant transformation are poorly understood on this disorder, but they seem to confer the
neoplastic cells a growth advantage over the normal marrow cells. Cytogenetics and molecular analysis
have defined several cytogenetic and molecular groups in precursor B-cell ALL that correlate highly with
sensitivity to chemotherapeutic agents, response to therapy and outcome. (See Table 8.1) Gene expression
profiling experiments have demonstrated that these cytogenetic and molecular lesions define dramatically
distinct tumor subtypes. In precursor T-cell ALL such heterogeneity has been less well defined, although
recent insights into correlations between immunophenotype, certain genetic lesions, gene expression
profiles, and outcome seem to suggest that clinically significant disease subtypes do exist within this
tumor category as well. These important lesions which appear to be mutually exclusive can be
demonstrated for clinical purposes using conventional cytogenetics, molecular analysis (RT-PCR), and
FISH. Of note, some of these lesions, most notably the t(12;21) can be cryptic by conventional
cytogenetics and therefore at least one other method of analysis should be employed in precursor B-cell
ALL with apparently normal diploid karyotype.
Lymphoblastic lymphoma of any lineage is
characterized by a diffuse pattern of growth sometimes associated with a "starry-sky" appearance in at
least a portion of the infiltrate. Associated fibrosis may be present in some cases. The lymphoma cells
are usually small to intermediate in size, with scanty cytoplasm, round to irregular nuclear outlines,
finely clumped nuclear chromatin and inconspicuous or single small ('pinpoint') nucleoli. Mitotic
figures may be frequent. In rare cases, especially in precursor B-cell ALL involving bone marrows, the
lymphoma cells may be large, with pleomorphic nuclei, mimicking large B-cell lymphoma. Of note, in bone
marrow aspirate samples, the ALL have been divided morphologically in L1 and L2 subtypes, depending on
blast size, amount of cytoplasm, pattern of chromatin and presence of nucleoli (FAB classification).
These categories do not correlate with biologically significant entities and appear to be of no use at
the present time.
LBL/ALL analyzed by flow cytometry typically expresses B-lineage antigens, including CD19,
CD22, CD24, and cytoplasmic CD79a. CD20 expression ranges from negative to weakly positive. In
addition, most tumors express CD10, CD34, and Tdt. Immunoglobulin expression, when present, is
restricted to the mu heavy chain (Ig mu), with no associated light chain expression or restriction. The
Ig mu may be present only in the cytoplasm, or in a small subset of cases ('transitional pre-B ALL') may
be weakly expressed on the blast surface. Immunohistochemical analysis of paraffin-embedded tissue
typically shows these tumors to be positive for Tdt, CD10, CD34, CD79a and negative for CD20 and CD3.
Stains for T-cell antigens usually highlight only scattered mature T-cells. Importantly, while most
neoplasms show weak CD45 expression which can be demonstrated by both modalities, a subset of tumors
(most commonly those associated with hyperdiploid karyotypes) are negative for CD45. Precursor T-cell LBL/ALL analyzed by flow cytometry shows a range of antigen
expression profiles. All neoplasms show expression of weak CD45, cytoplasmic CD3, and surface CD2, CD7
and often CD5. There is variable expression of surface CD3 (usually weaker than that seen on normal
T-cells), Tdt, and CD34, with a significant subset of Tdt negative, CD34 negative tumors. T-cell LBL
mimicking the cortical thymocyte phenotype is also CD1a+, CD4+, CD8+, CD21+. Immunohistochemical
staining of paraffin-embedded tissues shows these neoplasms to be positive for Tdt, CD45 and CD3 (the
latter two weaker than the normal T-cells in the infiltrate), as well as CD2, CD5, and CD7. Some of the
tumors are positive for CD10 and/or CD1a.
Precursor B-cell/Precursor T-cell LBL/ALL (also See Table 8.2):
Precursor B-cell LBL/ALL
- Myeloid sarcoma
- Monoblastic sarcoma
- Burkitt lymphoma/leukemia.
- Non-hematopoietic small blue-cell tumors (in
- Mantle cell lymphoma (blastoid variant) – In adult
Precursor T-cell LBL/ALL in mediastinal masses (see Table 10.1):
- Benign precursor B-cells (hematogones) seen in reactive
conditions or following chemotherapy or bone marrow transplantation (in bone marrow, lymph nodes and
- Benign (normal) thymus associated with another type of
- Hodgkin lymphoma
- Diffuse large B-cell lymphoma, primary mediastinal.
Table 8.1: Cytogenetic and Molecular Groups Important in Risk Stratification in Precursor
B-cell Acute Lymphoblastic Leukemia
|Cytogenetic abnormality ||Molecular lesion ||Prognostic Significance|
|t(9;22)(q34;q11.2)* ||BCR-ABL ('ALL-type') ||Unfavorable|
|t(12;21)(p13;q22) ||TEL-AML1 ||Favorable|
|t(1;19)(q23;p13.3) ||PBX-E2A ||Unfavorable**|
|t(4;11)(q21;q23) ||AF4-MLL ||Unfavorable|
|Hyperdiploid (>50 chromosomes) ||Not known ||Favorable|
|Hypodiploid (<46 chromosomes ||Not known ||Unfavorable|
* The Philadelphia chromosome
** With the current therapies the outcome of this type of translocation has improved to standard risk.
Table 8.2: Differential Diagnosis of Hematopoietic Neoplasms with Blastic Morphology
|Neoplasm ||CD45 ||Tdt ||CD79a ||CD3 ||MPO ||Lysozyme ||CD43 ||CD20 ||CyclinD1|
|Prec. B-LBL/ALL ||-/ weak+ ||+ ||+ ||- ||- ||- ||-/+ ||-/ weak+ ||-|
|Prec. T-LBL/ALL ||weak+ ||+/- ||-/weak+ ||weak+ ||- ||- ||+ ||- ||-|
|Myeloid sarcoma ||weak+/ negative ||- ||- ||- ||+ ||-/+ ||+ ||- ||-|
|Monoblastic sarcoma ||+ ||- ||- ||- ||- ||+ ||+ ||- ||-|
|Mantle cell lymphoma, blastic ||+ ||- ||+ ||- ||- ||- ||+ ||+ ||++|
Abbreviations: LBL/ALL – lymphoblastic lymphoma/leukemia.