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Precursor T-Cell Lymphoblastic Lymphoma
28 Precursor T-Cell Lymphoblastic Lymphoma John W. Sweetenham, M.D.
Precursor T-cell lymphoblastic leukemia/lymphoma is a neoplasm of T lymphoblasts. Until recently, the designation of lymphoblastic lymphoma was used to describe precursor B- and T-cell tumors with predominant lymph node involvement. Since the clinical distinction between lymphoblastic lymphoma and leukemia is arbitrary, and since these entities are identical at the morphologic, immunophenotypic, and molecular level, the World Health Organization classification has unified these entities as precursor B- or T-cell lymphoblastic leukemia/lymphoma. Lymphoblastic lymphoma is a clinically aggressive disease, frequently presenting with bulky mediastinal disease, and with a predilection for central nervous system (CNS) and bone marrow involvement. With the use of dose-intensive multiagent chemotherapy regimens, with CNS prophylaxis, with or without stem cell transplantation, long-term disease-free survival is achieved in 50% to 60% of adult patients with this disease.
FREQUENCY Lymphoblastic lymphoma accounts for about 2% of all nonHodgkin’s lymphomas.1 About 85% to 90% of adult cases are of T-cell phenotype, and occur most frequently in adolescent and young adult males.2–5 The median age at diagnosis is around 20 years, with most series reporting male predominance. There have been no recent reports suggesting a change in the incidence of this disease.
DIAGNOSIS Most cases of lymphoblastic lymphoma are diagnosed based on cellular morphology and flow cytometry or immunophenotyping. Lymphoblastic lymphoma is composed of medium-sized cells with finely dispersed chromatin and little cytoplasm3 with inconspicuous nucleoli. High mitotic activity with frequent apoptotic bodies that often results in a “starry sky” pattern is characteristic. Differential diagnosis includes lymphocyte-rich thymoma, which may be problematic since the lymphoid cells in both tumors have a thymic T-cell phenotype. However, the cytology of the cells is generally different, and the characteristic epithelial distribution of thymoma is not seen in lymphoblastic lymphoma. Most lymphoblastic lymphomas are tumors of precursor T lymphocytes,6,7 and express CD7, CD5, and CD2. CD3 is often present in the cytoplasm, but surface expression of CD3 is rare.8 By immunocytochemistry, most cases are CD3positive, while the sCD3-negative, cCD3+ phenotype is best demonstrated by flow cytometry. CD4 and CD8 can be expressed in any combination. Expression of non–lineage456
specific immature markers such as TdT or CD99, or in some cases CD34,9,10 is the most reliable way of distinguishing lymphoblastic lymphoma from peripheral T-cell lymphomas. If present, CD1a is relatively specific. Most T-lymphoblastic lymphomas have clonal T-cell receptor gene rearrangements, most commonly TCRd. However, gene rearrangement studies have a limited role in the diagnosis of this disease. Many precursor T-cell lymphoblastic lymphomas have translocations involving the Tcell receptor gene. About one-third of patients with T-lymphoblastic lymphoma have translocations involving the alpha and delta Tcell receptor loci at 14q11.2, the beta locus at 7q35, and the gamma locus at 7p14-5,11 resulting in juxtaposition of promoter and enhancer elements producing high levels of Tcell receptor gene expression, with transcription factor genes such as HOX11/TLX1, TAL1/SCL, TAL 2, and LYL 1.12–14 Gene expression profiles have identified molecular subtypes of precursor T-cell lymphoblastic disease that characterize different stages in thymocyte maturation, and which may identify prognostic subgroups.15 For example, patients with HOX11 expression show a pattern of gene expression corresponding to the early cortical thymocyte. This subgroup appears to have a more favorable clinical outcome, possibly related to the lower frequency of expression of the antiapoptotic bcl-2 gene. These cells are apparently developmentally arrested at a stage in which they are particularly sensitive to drug-induced apoptosis. In contrast, those samples with gene expression profiles associated with TAL1 or LYL1 expression resemble late cortical and early pro-T thymocytes, respectively, and show more drug resistance and correspondingly higher levels of bcl-2.
CLINICAL FEATURES Typical clinical features of T-lymphoblastic lymphoma include peak incidence in the second and third decades, male predominance, mediastinal involvement in 60% to 70% of patients, and pleural and pericardial effusions, the latter occasionally producing cardiac tamponade. Superior vena caval obstruction may also be a presenting feature. Peripheral lymph node involvement is present in 60% to 80% of patients at diagnosis, most commonly in cervical, supraclavicular, and axillary regions. Bone marrow and CNS involvement are frequent. In a recent study, 21% of adult patients with lymphoblastic lymphoma had bone marrow involvement at presentation,16 although it is important to emphasize that the reported inci-
Precursor T-cell lymphoblastic leukemia/lymphoma is a neoplasm of T lymphoblasts. Until recently, the designation of lymphoblastic lymphoma was used to describe precursor B- and T-cell tumors with predominant lymph node involvement. Since the clinical distinction between lymphoblastic lymphoma and leukemia is arbitrary, and since these entities are identical at the morphologic, immunophenotypic, and molecular level, the World Health Organization classification has unified these entities as precursor B- or T-cell lymphoblastic leukemia/lymphoma. Lymphoblastic lymphoma is a clinically aggressive disease, frequently presenting with bulky mediastinal disease, and with a predilection for central nervous system (CNS) and bone marrow involvement. With the use of dose-intensive multiagent chemotherapy regimens, with CNS prophylaxis, with or without stem cell transplantation, long-term disease-free survival is achieved in 50% to 60% of adult patients with this disease.
FREQUENCY Lymphoblastic lymphoma accounts for about 2% of all nonHodgkin’s lymphomas.1 About 85% to 90% of adult cases are of T-cell phenotype, and occur most frequently in adolescent and young adult males.2–5 The median age at diagnosis is around 20 years, with most series reporting male predominance. There have been no recent reports suggesting a change in the incidence of this disease.
DIAGNOSIS Most cases of lymphoblastic lymphoma are diagnosed based on cellular morphology and flow cytometry or immunophenotyping. Lymphoblastic lymphoma is composed of medium-sized cells with finely dispersed chromatin and little cytoplasm3 with inconspicuous nucleoli. High mitotic activity with frequent apoptotic bodies that often results in a “starry sky” pattern is characteristic. Differential diagnosis includes lymphocyte-rich thymoma, which may be problematic since the lymphoid cells in both tumors have a thymic T-cell phenotype. However, the cytology of the cells is generally different, and the characteristic epithelial distribution of thymoma is not seen in lymphoblastic lymphoma. Most lymphoblastic lymphomas are tumors of precursor T lymphocytes,6,7 and express CD7, CD5, and CD2. CD3 is often present in the cytoplasm, but surface expression of CD3 is rare.8 By immunocytochemistry, most cases are CD3positive, while the sCD3-negative, cCD3+ phenotype is best demonstrated by flow cytometry. CD4 and CD8 can be expressed in any combination. Expression of non–lineage456
specific immature markers such as TdT or CD99, or in some cases CD34,9,10 is the most reliable way of distinguishing lymphoblastic lymphoma from peripheral T-cell lymphomas. If present, CD1a is relatively specific. Most T-lymphoblastic lymphomas have clonal T-cell receptor gene rearrangements, most commonly TCRd. However, gene rearrangement studies have a limited role in the diagnosis of this disease. Many precursor T-cell lymphoblastic lymphomas have translocations involving the Tcell receptor gene. About one-third of patients with T-lymphoblastic lymphoma have translocations involving the alpha and delta Tcell receptor loci at 14q11.2, the beta locus at 7q35, and the gamma locus at 7p14-5,11 resulting in juxtaposition of promoter and enhancer elements producing high levels of Tcell receptor gene expression, with transcription factor genes such as HOX11/TLX1, TAL1/SCL, TAL 2, and LYL 1.12–14 Gene expression profiles have identified molecular subtypes of precursor T-cell lymphoblastic disease that characterize different stages in thymocyte maturation, and which may identify prognostic subgroups.15 For example, patients with HOX11 expression show a pattern of gene expression corresponding to the early cortical thymocyte. This subgroup appears to have a more favorable clinical outcome, possibly related to the lower frequency of expression of the antiapoptotic bcl-2 gene. These cells are apparently developmentally arrested at a stage in which they are particularly sensitive to drug-induced apoptosis. In contrast, those samples with gene expression profiles associated with TAL1 or LYL1 expression resemble late cortical and early pro-T thymocytes, respectively, and show more drug resistance and correspondingly higher levels of bcl-2.
CLINICAL FEATURES Typical clinical features of T-lymphoblastic lymphoma include peak incidence in the second and third decades, male predominance, mediastinal involvement in 60% to 70% of patients, and pleural and pericardial effusions, the latter occasionally producing cardiac tamponade. Superior vena caval obstruction may also be a presenting feature. Peripheral lymph node involvement is present in 60% to 80% of patients at diagnosis, most commonly in cervical, supraclavicular, and axillary regions. Bone marrow and CNS involvement are frequent. In a recent study, 21% of adult patients with lymphoblastic lymphoma had bone marrow involvement at presentation,16 although it is important to emphasize that the reported inci-