The majority of T-LBL patients presents with complaints resulting from a space-occupying mediastinal mass that may assume considerable dimensions upon diagnosis. In fact, this mediastinal mass often provokes bilateral pleural effusion and pericardial effusion, which, in turn, may cause dyspnea, cough, chest pain, attenuation of breath sounds and impaired resonance as assessed by means of percussion. Eventually, affected individuals may develop superior vena cava syndrome. The latter comprises distension of neck veins and raised jugular venous pressure as well as facial edema. The second most common site of solid tumor development in T-LBL patients are cervical, supraclavicular, and axillary lymph nodes. Tumor growth in non-lymphatic tissues is not characteristic of early T-LBL. If observed, liver and spleen are primarily affected. Neoplasms of the skin, tumors affecting the head and neck region, the bones, kidneys or gonads have only occasionally been noted in this context [10]. However, disease progression increases the risk of central nervous system compromise, and this organ system is usually the first site of relapse. Furthermore, the degree of bone marrow involvement seems to correlate with the incidence of lymphoma-associated brain and spinal cord tumors. Bone marrow involvement is detected upon diagnosis in about two thirds of T-LBL patients, and bone marrow blast counts are below 25%. Of note, T-LBL patients may present with multiple tumors, e.g., a mediastinal mass may be accompanied by neoplastic lymphadenopathy. Patients may additionally present constitutional symptoms like fatigue, fever, night sweats and weight loss.

Diagnostic imaging is of major importance to evaluate which organs are compromised by the disease. In this context, computed tomography scans are usually recommended to visualize the thoracic cavity; fluorodeoxyglucose positron-emission tomography is highly valuable for the detection of neoplastic lymphadenopathy, and magnetic resonance imaging is mainly used to examine the central nervous system. Histopathological analysis of biopsy samples taken from affected lymph nodes or solid tumors may be required to define the origin of tumor cells. Furthermore, bone marrow and cerebrospinal fluid specimens have to be analyzed to confirm or rule out bone marrow involvement, T-ALL, and central nervous system compromise. In order to assess the general condition of the patient and to evaluate organ function, laboratory analyses of blood samples should be performed.

Findings obtained by those means may be used for tumor staging according to St Jude's staging classification for childhood non-Hodgkin lymphoma (Murphy staging) or the Ann Arbor staging system in pediatric and adult patients, respectively [13] [14]. These staging systems consider the following:

• Sites of tumor growth
• Tumors in thoracic and/or abdominal cavity
• Nodal or extranodal presentation
• Multiple organ involvement
• Involvement of the bone marrow and/or central nervous system
• Resectability of solid tumors

Distinct protocols have been applied to treat T-LBL patients. Best results in case of childhood lymphoma have been achieved applying the protocols described by Reiter et al. [2]. In brief, pediatric patients were subjected to multi-agent chemotherapy adapted to the severity of the disease (stage I/II or stage III/IV), and time passed since the initiation of treatment:

• Induction, nine weeks of cyclophosphamide, daunorubicin, vincristine, prednisone plus L-asparaginase, cytarabine, mercaptopurine, methotrexate
• Extracompartment-protocol M comprising the application of mercaptopurine and methotrexate for eight weeks
• Re-induction in case of stage III/IV disease, consisting of cyclophosphamide, hydroxydaunorubicin, vincristine, dexamethasone plus L-asparaginase, cytarabine, thioguanine, methotrexate for seven weeks
• Cranial radiation therapy in case of stage III/IV disease, due to relatively high risks of spread to the central nervous system, an unfavorable prognostic factor [10]
• Maintenance therapy with mercaptopurine and methotrexate up to a total treatment period of two years

For adults diagnosed with T-LBL, similar protocols have been described [1]. Moreover, hematopoietic stem cell transplantation may be carried out after induction [3] [12].

While a determined regimen may be chosen upon diagnosis and staging, modifications may become necessary depending on the patient's response to therapy. Percentage of tumor regression, properties of residual tumors and resectability are primarily considered to this end. Available data indicate intense induction and consolidation to be crucial for success.

T-LBL is an aggressive neoplasm. For a long time, it has been associated with a poor outcome, but recently, event-free survival rates of up to 90% have been reported for pediatric patients [2]. In adults, such results have not yet been achieved, but there is an encouraging trend towards a better outcome. Recently, five- and seven-year overall survival rates of 42 and 51%, respectively, have been documented for adult patients [1] [3]. Unfortunately, the chance of survival drops drastically upon a relapse, e.g., to about 10% in case of childhood T-LBL [11]. Furthermore, female gender has been related to shorter survival, and it is tempting to speculate that this observation results from female patients being significantly older than men diagnosed with T-LBL [3]. Selected adult patients may benefit from hematopoietic stem cell transplantation [12].

Malignant transformation of T cell precursors accounts for the development of T-LBL, and it has been speculated that such events may be triggered by exposure to radiation, by pesticides, congenital or acquired immunosuppression [5].

Chromosomal translocations involving promoters and enhancers of genes encoding for T cell receptor chains are frequently observed. Consequently, transcription factors like CDKN2A/2B, FBXW7, HOX11/TLX1 (homeobox 11/T-cell leukemia homebox 1), HOX11L2/TLX3 (homeobox 11-like 2/T-cell leukemia homebox 3), LYL1 (lymphoblastic leukemia-derived sequence 1), NOTCH1, and TAL1/SCL (T-cell acute lymphocytic leukemia 1/stem cell leukemia) are put under the control of those regulatory sequences. These chromosomal aberrations are associated with dysfunctional regulation of cell growth, division and differentiation. Interestingly, the precise mutations underlying an individual case of T-LBL seem to correlate with the outcome. For instance, NOTCH/FBXW7 are encountered in about half of T-LBL cases and are related to a good prognosis [6]. About a fourth of T-LBL patients shows chromosomal anomalies involving HOX11L2/TLX3, which may predict a worse outcome [7].

T-LBL shows a bimodal age distribution, with higher incidence rates in people younger than 20 years and older than 50 years. With regards to pediatric patients, about one in three cases of non-Hodgkin lymphoma corresponds to T-LBL. This tendency is not reflected in the overall population, where T-LBL is considered a rare type of non-Hodgkin lymphoma that accounts for only 2% of cases. The overall incidence of lymphoblastic lymphoma has been estimated to 0.1-0.2 per 100,000 person-years, with the vast majority of those cases corresponding to T-LBL [8].

Males are affected more often than women. While the median age of T-LBL patients has been reported to be 40 years, females diagnosed with this lymphoproliferative disease are significantly older than males (e.g., 66 vs. 37 years as observed in Sweden [3]). Although racial predilection has been reported for other lymphoproliferative diseases, no significant differences have been encountered regarding the T-LBL incidence in African, Asian and Caucasian inhabitants of the United States [9]. In contrast, T-LBL incidence has been reported to correlate with socioeconomic development.

T-LBL is characterized by an uncontrolled proliferation of lymphoblasts, whose belonging to the T cell lineage may be demonstrated by immunophenotyping. Immunohistochemical staining or flow cytometry may be applied to this end, with biopsy samples, pleuropericardic effusion specimens or other body fluids being best suited for testing [10]. Tumor cells obtained from T-LBL patients generally test positive for CD1a (cortical T cells) or CD3 (non-cortical T cells), whereas CD2 expression is frequently lost. CD4 and CD8 are not specific for T cells, but are not expressed by B cells. Staining for CD10 and CD34 may yield positive results in both T cell and B cell lymphoma. In few cases, mixed immunophenotypes and expression of markers of at least two distinct hematopoietic lineages may be encountered. In sum, T-LBL are highly heterogenous, tumor cells differ in chromosomal aberrations and maturity, and there is no one panel of markers expressed in any case. While the determination of the immunophenotype is of major importance for the diagnosis and classification of lymphoma, it has not yet been possible to relate the respective findings with the patient's response to therapy and outcome [2].

No specific measures can be recommended to prevent T-LBL.

T-cell lymphoblastic lymphoma (T-LBL), previously designated precursor T-cell lymphoblastic lymphoma and sometimes also referred to as T-lymphoblastic lymphoma, is a rare lymphoproliferative disorder. According to the current classification of tumors of hematopoietic and lymphoid tissues, as published by the World Health Organization, T-LBL is a type of non-Hodgkin lymphoma associated with solid tumors in lymphatic tissues, hematological alterations and bone marrow involvement. In this context, T-LBL may be distinguished from T-cell acute lymphoblastic leukemia (T-ALL), with the two diseases characterized by bone marrow involvement below and above 25%, respectively [1]. Furthermore, they differ with regards to predominant lymphocytic phenotypes and gene expression profiles. In T-LBL, cortical and mature T cells prevail, whereas immature lymphocytes are more frequently encountered in T-ALL patients. There is no consensus whether these differences do indeed justify the definition of two malignant neoplasms, or whether they account for distinct forms of a single entity.

In any case, therapeutic regimens for T-LBL have almost exclusively been derived from protocols established for the treatment of T-ALL. They comprise CHOP chemotherapy, i.e., administration of cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), prednisone or prednisolone; CHOEP chemotherapy, which includes the application of etoposide; and hematopoietic stem cell transplantation. With regards to the success of those therapies, survival rates reported in literature speak for themselves: Intensive T-ALL therapy has been shown to be an effective treatment option for childhood T-LBL, and a five-year event-free survival rate of 90% has been achieved [2]. In a retrospective study recently conducted in Sweden, five-year overall survival in adults diagnosed with T-LBL has been observed to be 42% [3]. In contrast, in the 1980s, T-LBL has been described as an aggressive neoplasm with a median survival of about one year [4].

T-cell lymphoblastic lymphoma (T-LBL) is a rare lymphoproliferative disorder. It is triggered by chromosomal aberrations that lead to dysfunctional regulation of T cell growth, division and differentiation, but to date, little is known about the causes of the respective translocations of DNA sequence segments.

T cells or T lymphocytes are immune cells that fulfill a myriad of functions: They are able to recognize degenerated and foreign cells and may mediate their destruction, they may induce an immune response involving antibody-producing B lymphocytes, and they may also suppress such an immune response when the threat has past. Early T cell precursors may be encountered in the bone marrow, but these cells mature in an immune organ called thymus. The thymus is located in the mediastinum, close to the heart in the thoracic cavity.

The aforementioned chromosomal translocations generally occur in T cells undergoing maturation processes in the thymus. Because they proliferate in an uncontrolled manner, a solid mediastinal tumor may form, and this is indeed the most frequent finding in T-LBL patients. However, T cells may reach any tissue of the human body, and tumors may also grow in lymph nodes, liver, spleen and other organs. If tumor cells infiltrate the central nervous system or the bone marrow, the patient's prognosis worsens significantly.

Most patients are adolescents or adults aged 50 years and older. Upon diagnosis of T-LBL - which is a long process involving diagnostic imaging, histopathological analysis of biopsy specimens and analysis of bone marrow and cerebrospinal fluid - an appropriate treatment regimen is chosen. Most patients have to undergo long-term multi-agent chemotherapy, but protocols have repeatedly been adjusted to the needs of T-LBL patients and today, five-year-survival rates of 90% and 50% in pediatric and adult patients, respectively, may be achieved.

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