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The co-occurrence of thymoma and T-lymphoblastic lymphoma/leukemia is an extremely rare but previously reported association that poses a diagnostic and therapeutic challenge. We describe a 67-year-old patient with long-standing untreated B1 thymoma that presented with constitutional symptoms and a painless soft tissue mass on the right chest wall. Pathological analysis of the biopsy from the mass demonstrated T-lymphoblastic leukemia/lymphoma. The patient went through a complicated course, was refractory to several lines of therapy, and eventually underwent allogeneic hematopoietic stem cell transplantation in complete remission from a matched related donor. The association between thymoma and malignant neoplasms has been described in the literature, most notably with colorectal adenocarcinoma and thyroid cancer. Thymoma-associated leukemia is, however, extremely unusual, with limited reports in the literature. Distinguishing between thymoma and leukemia can be challenging and often requires meticulous diagnostic efforts. For patients with a past history of thymoma, awareness of this particular association should be bared in mind to allow earlier diagnosis and therapy.

Mediastinal masses commonly present in children and may pose diagnostic challenges, particularly with limited sampling. This article aids the pathologist by reviewing the hematologic differential diagnosis of a pediatric mediastinal mass, along with ancillary testing useful for rendering the correct diagnosis. A review of the more common lymphomas is presented, including classic Hodgkin lymphoma, T-lymphoblastic leukemia/lymphoma, and primary mediastinal (thymic) large B-cell lymphoma, along with brief mentions of less common entities such as gray zone lymphoma and thymoma as well as non-neoplastic conditions such as benign cysts and infections.

Gamma-delta (γδ) T-cell lymphomas are very rare and aggressive neoplasms. We describe here a challenging case of γδ T-cell neoplasm composed of γδ mature T-cells and γδ precursor T-cells with marked eosinophilia that is inapplicable to the current 2016 World Health Organization (WHO) classification. A 3-year-old female child who was presented with fever and marked leukocytosis. Peripheral blood smear showed marked lymphocytosis, marked eosinophilia, neutrophilia, monocytosis, and 5% circulating blasts. CT scan showed anterior mediastinal mass, lymphadenopathy, and hepatosplenomegaly. The patient underwent a bone marrow examination and a biopsy taken from the mediastinal mass. Peripheral blood and bone marrow findings were consistent with a γδ T-cell neoplasm with increased blasts and eosinophilia. The patient was sequentially treated with imatinib (tyrosine kinase inhibitor), acute lymphoblastic leukemia protocol (BFM 2009) then shifted to lymphoma protocol (LMP 96). In conclusion, we report a unique rare case of γδ T-cell neoplasm with a combination of mature and immature γδ T-cells and eosinophilia that is inapplicable to the current 2016 WHO classifications. This case raises a challenging concept of a mature T-cell lymphoma arising in an immature T-cell neoplasm. It also highlights the need to target all neoplastic components to eradicate the disease.

AIMS An indolent T-lymphoblastic proliferation (iT-LBP) is a benign, reactive expansion of immature terminal deoxynucleotidyl transferase (TdT)-positive T cells found in extrathymic tissues. iT-LBP can be challenging to distinguish from malignant processes, specifically T-lymphoblastic lymphoma (T-LBL), given the overlapping clinical and histological features. Recently, it has been shown that LIM domain only 2 (LMO2) is overexpressed in T-LBL but not in reactive immature TdT+ T cells in the thymus. On the basis of these findings, the aim of this study was to investigate the expression of LMO2 by using immunohistochemistry and its role in differentiating iT-LBPs from T-LBLs. METHODS AND RESULTS We retrospectively identified cases of iT-LBP and T-LBL from the pathology archives of four institutions. Seven iT-LBP cases (including five new cases that have not been reported in the literature) and 13 T-LBL cases were analysed. Clinical, morphological, immunophenotypic and molecular data were analysed. Immunohistochemical staining with LMO2 was performed on all iT-LBP and T-LBL cases. A review of five new iT-LBP cases showed similar morphological, immunophenotypic and molecular features to those of previously reported cases. All iT-LBP cases were negative for LMO2 (0/7), whereas 92% of T-LBL cases (12/13) expressed LMO2; the sensitivity was 92% (confidence interval 64-100%) and the specificity was 100% (confidence interval 59-100%). CONCLUSION We confirm previously published findings that iT-LBP cases show highly overlapping morphological and immunophenotypic features with T-LBL. Importantly, LMO2 expression is a sensitive and specific marker with which to rule out iT-LBP.

In this review, we discuss applications of flow cytometric immunophenotyping (FCI) in the diagnostic evaluation and posttreatment monitoring of B and T lymphoblastic leukemia/lymphoma. We describe practical approaches to FCI at the time of diagnosis, with an emphasis on blast identification, lineage assignment, and distinction of B and T lymphoblastic leukemia/lymphoma from their morphologic and immunophenotypic mimics. We further review flow cytometric assays for the detection of minimal or measurable residual disease (MRD) after treatment, and illustrate both standard approaches, and newer strategies for improving sensitivity and circumventing the loss of immunophenotypic targets after immunotherapy. © 2019 International Clinical Cytometry Society.

The mediastinum contains essentially all major intrathoracic organs except for the lungs. A variety of both benign and malignant tumors can involve the mediastinum, of which lymphoma is the most common malignancy. Compared to secondary mediastinal involvement by systemic lymphomas, primary mediastinal lymphomas are less common with several specific entities that are mainly confined to mediastinal lymph nodes, and/or thymus. This review will summarize the clinical, histologic, immunophenotypic and molecular genetic features of the most common and most aggressive primary mediastinal lymphomas as well as provide suggested immunohistochemistry panels and differential diagnoses.

Introduction/Objective T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a malignancy arising from immature precursor T cells with T-ALL involving bone marrow/blood and T-LBL occurring in the thymus and nodal/extranodal sites. Studies have now revealed >100 recurrently altered genes that are not necessarily disease initiating but can provide diagnostic, prognostic, and predictive information which can then be utilized in personalized therapy. Methods/Case Report Next-generation sequencing was performed on DNA and/or RNA extracted from blood/marrow aspirates or tissue at an external CLIA-certified, CAP-accredited laboratory. The hematology panel sequenced DNA of 406 genes, introns of 31 gene rearrangements, and RNA of 265 genes. This retrospective single-center study highlights salient findings noted in genomic profiles of 15 T-ALL/LBL cases out of 83 total patients with ALL from 2018-2021. While the majority were B-ALL cases, T-ALL accounted for 18%, and all but 1 case were pediatric patients (ages 9-21 years). Results (if a Case Study enter NA) In our pediatric cohort (14 patients; 9 males, 5 females), as in literature, NOTCH signaling was most frequently involved with NOTCH1 (50%) and FBXW7 (36%) mutations, followed by those in cell cycle process CDKN2A/2B (36%) and PTEN (28%) mutations. Other mutations: PHF6 (21%), BCOR and TAL1 (14%) each. The prognostic effect of mutations: NOTCH1 favorable, FBXW7 no effect but trend toward favorable when FBXW7 co-occurs with NOTCH1 while PTEN is unfavorable (3 patients had relapses). Some unusual or useful findings: a patient diagnosed initially as AML with aberrant CD3 was re-classified as early T-cell precursor ALL, supported by RELN mutation (occurs in 4% ETP-ALL). The adult with NOTCH1 and BCOR mutations in addition to BCR-ABL1 fusion was diagnosed as having T-ALL blasts with CML. We could not study detailed nuances in mutational profiles of T-ALL vs T-LBL with only 1 case of T-LBL showing FBXW7, PTEN, NF1, RB1, BCOR and NRAS mutations (latter is typically noted in pediatric T-LBL cases). Conclusion Clinical molecular testing in our pediatric T-ALL patients revealed gene alterations that provide refinement of diagnosis, prognosis, and risk stratification. It also contributes a useful data set for further analysis and potential use of clinically actionable therapeutic targets in some cases. Longer term follow-up incorporating therapy and outcomes information would be valuable.

Rationale: Primary non-Hodgkin lymphoma (NHL) of the testes is rare, representing about 9% of testicular neoplasms and 1% to 2% of non-Hodgkin lymphomas. Patient concerns: A previously healthy 47-month-old boy came to our institution for 3 months unilateral testicular swelling without tenderness. After preliminary examination, inguinal orchiectomy was performed to resect the right scrotal mass. The histopathological diagnosis of high-grade lymphoma was rendered and paraffin blocks were sent for immunophenotyping. Diagnosis: The final diagnosis by histopathological combined with immunohistochemical staining revealed primary testicular T-cell lymphoblastic lymphoma (St Jude Children's Research Hospital Staging System, stage I). Interventions: The patient was treated with right inguinal orchidectomy followed by chemotherapy (SMCC-2011 protocol modified based on the BFM-90/95 regimen from Germany) without prophylactic radiotherapy to the contralateral testis. Outcomes: After 36 months of follow-up, the patient is now disease-free without any complication. Lessons: T-lymphoblastic lymphoma should be considered in the differential diagnosis of testicular masses in children. Intensive chemotherapy may improve the prognosis of such patients.

T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) accounts for approximately 15% of pediatric and 25% of adult ALL. While the underlying frequency of KMT2A (MLL) gene rearrangements has been identified in approximately 4-8% of T-ALL/LBL cases, a paucity of literature is available to characterize further the KMT2A rearrangements in pediatric/young adult T-ALL/LBL. A 10-year retrospective review was performed to identify KMT2A rearrangements in specimens sent for T-ALL/LBL fluorescence in situ hybridization studies in patients under the age of 30 years. Of 806 T-ALL/LBL FISH studies performed on unique individuals, 27 (3.3%) harbored KMT2A rearrangements. Nineteen patients were male and eight were female (M:F ratio, 2.4:1) with ages ranging from 1 to 20 years (mean 12, median 12). Of the 27 cases, nine (33%) had KMT2A/MLLT1 fusions, eight (30%) had KMT2A/AFDN fusions, two (7%) had KMT2A/ELL fusions, and one (4%) had a KMT2A/MLLT10 fusion. In addition, five (19%) had KMT2A rearrangements with unidentified gene fusion partners and two (7%) had 3'KMT2A deletions. Our results indicate that MLLT1 and AFDN account for the majority (63%) of KMT2A gene partners in pediatric/young adult T-ALL/LBL, while no KMT2A/AFF1 or KMT2A/MLLT3 fusions were observed despite their common identification in B-ALL and acute myeloid leukemia, respectively. In addition to diagnostic and prognostic value, detecting specific KMT2A fusions may also be of clinical importance in the era of targeted therapies.

Immunophenotypic analysis using multiparameter flow cytometry is an indispensable tool for diagnosis and management of acute leukemia. Mouse models have been widely used for medical research for more than 100 years and are indispensable for leukemia research. However, immunophenotypic analysis of murine leukemia was not always performed in published studies, and blast gating for isolation of blasts was shown only in very few studies. No systemic characterization of all types of murine acute leukemia in large cohorts by flow cytometry has been reported. In this study, we used flow cytometry to comprehensively characterize murine acute leukemia in a large cohort of mice. We found that murine T-lymphoblastic leukemia/lymphoma (T-ALL) exhibits a distinctive “blast gate” (CD45bright) with CD45/side scatter gating that differs from the “blast gate” (CD45dim) of human T-ALL. By contrast, murine B-lymphoblastic leukemia and acute myeloid leukemia show the same blast region (CD45dim) as human leukemia. Using blast cell gating, we for first time detected T-ALL development in FLT3-ITD knock-in mice (incidence: 23%). These leukemic cells were selectively killed by the FLT3 inhibitors crenolanib and midostaurin in vitro. These data suggest that FLT3-ITD plays a potential role in the pathogenesis of T-ALL and that FLT3-ITD inhibition is a therapeutic option in the management of patients with T-ALL. Our gating strategy for immunophenotypic analysis can be used for leukemogenesis and preclinical gene therapy studies in mice and may improve the quality of such analyses.

T lymphoblastic leukemia/lymphoma (T-ALL/LBL) is highly aggressive. Although intensive chemotherapies such as ALL-type regimens are commonly used, about half adult patients eventually relapse and die of T-ALL/LBL. Overwhelming evidences have confirmed that interim PET can predict survival outcomes and guide subsequent treatments in Hodgkin lymphoma. However, whether interim PET-CT can predict survival outcomes or not in T-ALL/LBL patients remains unclear. 47 adult patients of T-ALL/LBL were retrospectively reviewed. Interim PET-CT was done after induction therapy and evaluated according to the International Harmonization Project criteria. After induction therapy, interim PET-CT was positive in 19 patients (40.4%). After a median follow up time of 34 months, the 2-year and 3-year progression free survival (PFS) rate were 39% and 30%, respectively, and the 2-year and 3-year overall survival (OS) rate were 54% and 45%, respectively. Using Kaplan-Meier survival analysis, it was found that interim PET-CT positivity correlated with significantly inferior PFS and OS (2-year PFS rate for patients with positive or negative interim PET were 21.1% or 56.0%, respectively, p = 0.002; 2-year OS rate for patients with positive or negative interim PET were 31.6% or 63.7%, respectively, p = 0.010). However, there was no significant relationship between PFS, OS and bone marrow infiltration, lactate dehydrogenase level, and stages (p > 0.05). Interim PET-CT may predict PFS and OS in adult patients of T-ALL/LBL, which needs to be validated in prospective clinical trials. The optimal criteria for interim PET-CT evaluation and risk-adapted treatment strategy determined by interim PET-CT should be investigated in future clinical practice.

Leukemia cutis is uncommon in patients with acute lymphoblastic leukemia. It typically presents with dermal papules or subcutaneous nodules, with no epidermal or upper papillary dermal involvement on histopathology. We present an unusual clinical presentation of leukemia cutis, with annular plaques and epidermotropism.

Background Nelarabine has been used for the treatment of T-cell malignancies including T-acute lymphoblastic leukemia (T-ALL)/T-lymphoblastic lymphoma. However, the mechanisms that underlie the susceptibility or resistance to nelarabine have not been fully elucidated. The aim of this study was to determine the significance of nelarabine transport and metabolism in the context of nelarabine cytotoxicity. Procedure The expression profiles of six genes in the nelarabine pathway were analyzed in blast cells from six patients with T-ALL as well as in three T-ALL cell lines. In vitro cytotoxicity (LC50 of 9-β-d-arabinofuranosylguanine [ara-G]) was evaluated. Results The mRNA expression of ENT1, DCK, CDA, NT5C2, RRM1, and RRM2 in patients showed inter-individual variability and was not correlated with the LC50 of ara-G. However, the ratio of (ENT1 × DCK)/(CDA × RRM1) expression was significantly correlated with LC50 (r = –0.831, P = 0.0405). Conclusions Chemosensitivity to nelarabine is influenced by the balance of the expression of these four genes, and the ratio of their expression predicts the response of T-cell malignancies to nelarabine.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosomal instability disorder characterized by microcephaly, immunodeficiency, radiosensitivity and a very high predisposition to malignancy. The gene responsible for the disease, NBS1, is located on chromosome 8q21 and encodes a protein called nibrin. After identification of the gene, a truncating 5 bp deletion, 657-661delACAAA, was identified as the disease-causing mutation in patients with the NBS. In this report, we describe two patients with NBS and T-lymphoblastic leukemia/lymphoma in a Macedonian family. To the best of our knowledge, this is the first family with NBS reported from Macedonia. Both children presented with microcephaly, syndactyly and the development of T cell lymphoblastic lekemia/lymphoma at the age of 7 and 10 years, respectively. The molecular analysis of NBS1 genes in our patients showed homozygosity for the 657del5 mutation in the NBS1 gene. The parents were heterozygotes for the 657del5 mutation and they had no knowledge of a consanguineous relationship. The first child was treated with the International Berlin-Frankfurt-Münster (BFM)-Non Hodgkin lymphoma (NHL) protocol and achieved a complete remission that lasted for 21 months. Subsequently, he developed a medullar relapse with hyperleukocytosis and died due to lethal central nervous system (CNS) complications. The second child was treated according to the International Collaborative Treatment Protocol for Children and Adolescents with Acute Lymphoblastic Leukemia 2009 (AIOP-BFM ALL 2009) protocol. Unfortunately, remission was not achieved.

Rationale: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important treatment for hematological malignancies. Common complications are opportunistic infections and graft-versus-host disease (GVHD). Cytomegalovirus (CMV) is one of the most common causes of opportunistic infections. Patient concerns: A 30-year-old male was diagnosed with T-cell lymphoma after persistent cough and lymphadenopathy. Fever, abdominal pain, diarrhea, rash, and dyspnea occurred after HSCT. Diagnosis: The young man developed severe CMV infection with CMV detected in the bronchoalveolar lavage fluid and gastrointestinal tract. Interventions: Intravenous ganciclovir and high-dose glucocorticoids were administered after the patient was diagnosed with CMV pneumonia and enteritis. Outcomes: After 3 weeks, the young man died from respiratory failure and infectious toxic shock caused by severe CMV infection. Lessons: Patients after HSCT should be closely monitored CMV-DNA in blood and other specimen, and treated first if necessary, so as to avoid the occurrence of severe infections such as CMV gastroenteritis and pneumonia.

We report a case of a 62-year-old man with concurrent thymoma, thymic carcinoma, and T lymphoblastic leukemia/lymphoma. Computed tomography revealed a 5.5-cm anterior mediastinal mass, and surgical resection was performed. Histologically, the mass showed concurrent thymoma (type AB), thymic carcinoma, and T lymphoblastic leukemia/lymphoma. Lymphoma cells infiltrated in the left lung, pulmonary hilar lymph nodes, and involved bone marrow. The patient underwent chemotherapy for T lymphoblastic leukemia/lymphoma and achieved remission. One year after surgery, he remains free of both thymoma and thymic carcinoma, and T lymphoblastic leukemia/lymphoma remains complete remission under maintenance therapy. Thymoma and T lymphoblastic leukemia/lymphoma can combine in the same mass, although this is quite rare. At the time of the diagnosis of thymoma, additional attention should be directed toward lymphocytes in the background.

The BCR-PDGFRA fusion is a very rare event. To date, only eight cases of hematolymphoid neoplasms with the BCR-PDGFRA fusion gene have been reported. All cases except one had eosinophilia. We present the first case of T acute lymphoblastic leukemia with a t(4;22)(q12;q11.2) involving the BCR and PDGFRA genes, without associated eosinophilia. Radiology showed splenomegaly and extensive lymph node involvement. The patient rapidly achieved complete remission with treatment protocol for Philadelphia chromosome−negative acute lymphoblastic leukemia.

Background: T cell lymphoblastic leukemia/lymphoma with the initial symptom of effusion is an uncommon condition. It may present a diagnostic challenge as lymphoblastic cells mimic normal lymphocytes under a low-power microscopic view. Cases: Two cases are presented, both male, with the first aged 31 years and the second aged 54 years. Both initially presented with chest pain and shortness of breath, and CT scans found an anterior mediastinal mass and left pleural effusion in both subjects. Cytological smears of pleural fluid in each case showed monotonous small-to-medium-sized lymphoid cells with moderate chromatin condensation and round-to-convoluted nuclei. There were prominent apoptotic bodies and mitosis in both cases. Immunohistochemistry of cell blocks demonstrated their T cell lineage and lymphoblastic nature. Diagnosis of T cell lymphoblastic leukemia/lymphoma was determined by a 3-step algorithmic approach using complete panels of immunohistochemical markers (CD3, CD20, Ki-67, CD10, CD5, CD99, CD1a, CD34, CD4, CD8, TDT, CD7, CD2 and CD68). Conclusion: An algorithmic approach based on cytological morphology and immunophenotyping is an effective way to diagnose T cell lymphoblastic leukemia/lymphoma in patients with an initial symptom of pleural effusion and insidious cytological morphology.

International audience; Iron is an essential nutrient, acting as a catalyst for metabolic reactions that are fundamental to cell survival and proliferation. Iron complexed to transferrin is delivered to the metabolism after endocytosis via the CD71 surface receptor. We found that transformed cells from a murine PTEN-deficient T-cell lymphoma model and from T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LL) cell lines overexpress CD71. As a consequence, the cells developed an addiction toward iron whose chelation by deferoxamine (DFO) dramatically affected their survival to induce apoptosis. Interestingly, DFO displayed synergistic activity with three ALL-specific drugs: dexamethasone, doxorubicin, and L-asparaginase. DFO appeared to act through a reactive oxygen species-dependent DNA damage response and potentiated the action of an inhibitor of the PARP pathway of DNA repair. Our results demonstrate that targeting iron metabolism could be an interesting adjuvant therapy for acute lymphoblastic leukemia.

Introduction: Detection of minimal residual disease (MRD) in T-lymphoblastic leukemia/lymphoma (T-ALL) has been used in post-therapy monitoring and outcome prediction. Currently, multi-color flow cytometry is widely used for MRD detection with limit of detection (LOD) of 0.1 to 0.01% depending on the clinical implementation. However, flow cytometry assays require extensive training and experience for accurate interpretation and standardization is challenging. Next generation sequencing (NGS) assays with panels targeting the inherent polymorphism of the immunoglobulin genes have been applied for MRD detection in B cell neoplasms, including an assay for myeloma and B-ALL MRD detection developed by Adaptive Biotechnologies (Seattle, WA) that was granted FDA approval for clinical testing. We have published a similar approach for T-ALL MRD detection using the polymorphic T-cell receptor (TCR) genes. These assays offer higher sensitivity, easier standardization, and more objective interpretation. Here we present our comprehensive evaluation and validation of a T-ALL MRD assay using the Adaptive Biotechnologies immunoSEQ kit for potential clinical application. Methods: NGS was performed using the Adaptive Biotechnologies immunoSeq kit and illumina NextSeq 500 according to manufacturer's instruction. Quantification of T cell repertoire was performed using the Adaptive Biotechnologies analysis pipeline. A single TCRβ sequence with ≥19% frequency of the T-cell population in diagnostic samples was defined as a T-ALL clone. Positive MRD was defined as detection of one or more such T-ALL sequences having a 100% DNA sequence match in the corresponding MRD samples. T-ALL leukemic cells and normal T cells were sorted from 2 bone marrow aspirates and peripheral blood from 20 healthy donors, respectively. T-ALL cells were spiked into pooled normal T cells to create a series of diagnostic T-ALL standards and MRD T-ALL standards down to 0.001%. Prior to assaying the standards, a T-ALL specimen was assessed at 11 different DNA input levels ranging from 3-1000ng, and interference of non-T-cell DNA was tested. For all other assays, 800ng DNA was used in two independent hsTCRB replicates for T-ALL clone identification in diagnostic samples and 2,400ng DNA was used in six independent hsTCRB replicates for T-ALL clone detection in MRD samples. Within run precision was assessed by assaying all standards and 3 pairs of diagnostic and MRD samples in triplicate. Between run precision was assessed by assaying 1 standard and 4 samples on two different days by the same technologist. Intermediate precision was assessed by assaying 3 pairs of diagnostic and MRD samples by two different technologists. LOD was determined as the lowest frequency at which MRD could be detected in MRD standards and Limit of Quantitation (LOQ) determined as the level below which the coefficient of variation (CV) >25% in MRD standards. Results: The %CV for T-ALL quantification across the range of DNA input was 4.5%, suggesting independence of quantification from DNA input amount. Non-T-cell DNA has almost no impact on T-ALL quantification. T-ALL clones were detected with 100% concordance in diagnostic and MRD standards. The %CV of within and between run precision and intermediate precision were < 25% in T-ALL identification assay and all MRD detection assays except at 0.001% MRD, in which %CV was 43.8%. Quantification of T-ALL in both diagnostic and MRD standards were highly correlated with expected values (R2 = 0.96, slope = 0.89 and R2 = 1.00, slope = 0.88, respectively). T-ALL identification and MRD detection in specimens stored at 4°C or at room temperature for up to 14 days were within 25% CV as compared to fresh specimens. The assay was then performed on 40 diagnostic clinical T-ALL samples and T-ALL clonal sequences were identified in 34 samples (85%). Conclusions: The immunoSEQ assay is evaluated and technically validated for clinical application, but requires validation in a larger cohort of clinical samples with concurrent outcome data. The assay is suitable for roughly 70% T-ALL where TCRβ is rearranged. The assay LOD for T-ALL MRD detection is 0.001% and LOQ is 0.01%, offering the possibility of improved sensitivity and more objective interpretation. Disclosures No relevant conflicts of interest to declare.

Nelarabine, a purine analog with T-cell specific action, has been approved for relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL). This is a report of a single-arm phase 2 study conducted in adults (18-81 years of age) with relapsed/refractory T-ALL/LBL. After 1 or 2 cycles, 45 of 126 evaluable patients (36%) achieved complete remission (CR), 12 partial remission (10%), and 66 (52%) were refractory. One treatment-related death was observed, and 2 patients were withdrawn before evaluation. A total of 80% of the CR patients were transferred to stem cell transplantation (SCT). Overall survival was 24% at 1 year (11% at 6 years). After subsequent SCT in CR, survival was 31% and relapse-free survival 37% at 3 years. Transplantation-related mortality was 11%. Neurologic toxicities of grade I-IV/grade III-IV were observed in 13%/4% of the cycles and 16%/7% of the patients. This largest study so far with nelarabine in adults showed impressive single-drug activity in relapsed T-ALL/T-LBL. The drug was well tolerated, even in heavily pretreated patients. A high proportion of CR patients were transferred to SCT with low mortality but a high relapse rate. Exploration of nelarabine in earlier stages of relapse (eg, increasing minimal residual disease), in front-line therapy, and in combination is warranted.

This report concerns a unique case of a composite lymphoma composed of T-lymphoblastic leukemia/lymphoma (T-LBL) and diffuse large B-cell lymphoma (DLBCL) in a 72-year-old woman with generalized lymphadenopathy, splenomegaly and ascites. Laboratory findings showed increased lactate dehydrogenase and soluble interleukin-2 receptor. The biopsy specimen showed replacement of the normal architecture of the lymph nodes by a tumor containing a dual cell population composed of large lymphocytes and medium-sized lymphocytes. Sheets of large lymphocytes often were punctuated by clusters of medium-sized lymphocytes. Flow cytometry and immunohistochemical analysis showed a composite lymphoma with both T-LBL and DLBCL. The T-LBL expressed CD1a, CD3, CD4, CD8, and terminal deoxynucleotidyl transferase. The DLBCL expressed CD19 and CD20, CD23, bcl-2, bcl-6, MUM1 and immunoglobulin κ light chain. Polymerase chain reaction detected a monoclonal pattern of T-cell receptor γ and immunoglobulin heavy chain rearrangements in the same specimen. She received eight cycles of R-CHOP (rituximab+cyclophosphamide, doxorubicin, vincristine, prednisone) therapy and achieved complete remission. She has shown no signs of recurrence 20 months after the diagnosis. We describe here a very unusual and, to the best of our knowledge, an as yet never reported case of a primary composite lymphoma of T-LBL and DLBCL.

T-lymphoblastic leukemia/lymphoma (LBL and ALL) is a rare lymphoid malignancy typically presenting in adolescent and young adult males. Patients are traditionally treated with ALL-type protocols, with no consensus on the role of maintenance therapy, or allogeneic or autologous transplant. Outcome results are thus difficult to interpret. The successful use of intensified ALL protocols in patients25 years with lymphoblastic malignancies without transplant prompted the Haematology Unit at St James's Hospital (SJH) to change practice in 2005 from transplanting in first complete remission (CR1) to treating patients25 years with chemotherapy alone. We reviewed the outcome of patients treated before 2005 in order to compare the pre- and post-2005 management approaches in the future. This retrospective study included 31 patients with T-LBL treated from 1980 to 2004. The patients were divided into group A (16-25 years) and group B (25 years). Twenty-one patients had an allograft in CR1 (group A, n = 12 and group B, n = 9). For the allografted patients the 5-year EFS and OS was 57%, with a treatment related mortality of 10%. In conclusion, this series confirms that allograft in CR1 has an acceptable cure rate, and we will use these results to benchmark outcomes using pediatric-type protocols in the future.

Chromosome 1 band p32 (1p32) aberrations are common in T lymphoblastic leukemia/lymphoma (T-ALL/LBL). Two types of 1p32 aberrations include translocations with different partners and submicroscopic interstitial deletion. Both aberrations are known to result in TAL1 gene deregulation. The t(1;5)(p32;q31) is a rare translocation of 1p32 in T-ALL. We now present the second case of t(1;5)(p32;q31) in T-ALL, which was present as a primary cytogenetic abnormality, with a review of the relevant literature. Interestingly, neither the translocation of the TAL1 gene nor aberrant expression of TAL1 protein was detected by fluorescent in situ hybridization (FISH) and by immunohistochemical staining in this case.

Objectives: The diagnosis of T-lymphoblastic leukemia/lymphoma (T-ALL) involving the thymus can be difficult to establish since neoplastic T lymphoblasts show significant phenotypic overlap with both normal thymocytes and thymocytes from epithelial thymic neoplasms (thymomas). LIM Domain Only 2 (LMO2) gene translocations have been implicated in the pathogenesis of a small subset of T-ALLs, and LMO2 protein has recently been reported to be expressed in a large proportion of T-ALLs. Methods: In this study, we tested specificity of LMO2 for distinction between neoplastic and nonneoplastic T-precursor cells in thymus and bone marrow. Results: Our findings show that LMO2 is expressed in neoplastic lymphoblasts of T-ALL and is absent in thymocytes of normal thymuses or thymomas. Conclusions: LMO2 is therefore a useful marker for immunophenotypic assessment of thymic neoplasms.

Objectives To review important concepts from the 2013 Society for Hematopathology/European Association for Haematopathology Workshop session on T-acute lymphoblastic leukemia/T-lymphoblastic lymphoma (T-ALL/T-LBL). Methods Twenty-one submitted cases are reviewed and summarized, with emphasis on key diagnostic or biologic points, and supplemented with relevant literature citations. Results Early T-cell precursor (ETP)-ALL represented about one-third of all cases submitted. It is important to recognize ETP-ALL, because these patients have a poor prognosis if treated with standard therapy. A consensus immunophenotype has been developed to aid in the recognition of these cases. Other cases submitted illustrated rare entities, including two cases of Philadelphia chromosome–positive T-ALL, two cases of T-ALL associated with MYC translocations, and single cases illustrating various diseases. A subset of cases submitted illustrated issues related to differential diagnosis of T-ALL/T-LBL. Conclusions In view of the growing importance of molecular genetic analysis in the diagnosis and prognosis of T-ALL/T-LBL, it is important for pathologists to keep abreast of these developments. Currently, routine histopathology, immunophenotyping, conventional cytogenetic analysis, fluorescence in situ hybridization, and clonality testing are usually adequate to establish the diagnosis. However, as therapies become more targeted, assessment for relevant genetic abnormalities, either through candidate gene or broad-scale unbiased approaches, may become necessary.

The 2008 WHO classification scheme of hematolymphoid neoplasms recognizes a category of myeloid and lymphoid neoplasms (MLNs) with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1.1 The postulated cell of origin for PDGFRA or FGFR1-rearranged diseases is a pluripotent progenitor capable of giving rise to myeloid neoplasms (myeloproliferative neoplasms and acute leukemias) and to lymphoblastic leukemia/lymphoma. Historically, PDGFRB translocations have not been associated with malignancies of the lymphoid lineage. Myeloid neoplasms with abnormalities of PDGFRB have been described to have hematologic features of chronic myelomonocytic leukemia (CMML), sometimes with eosinophilia, or as various other myeloproliferative and/or myelodysplastic neoplasms.2 In recognition of this distinction, the classification scheme designates specific categories of “MLNs” with PDGFRA and FGFR1 rearrangement, but omits the word “lymphoid” from the PDGFRB-associated entity.1 To call attention to the rare occurrence of lymphoid and mixed MLNs with abnormalities of PDGFRB, we present the clinical and pathological details of 2 cases.

Undiagnosed neoplasms in childhood are rare causes of sudden and unexpected death. Deaths due to undiagnosed hematologic malignancies are limited to a small number of case reports. The following case of acute leukemia was diagnosed at forensic autopsy in a 5-year-old boy with no significant past medical history. He complained of nausea and vomiting 2 days before his death, with the subsequent development of fever. Meningitis was the initial suspected cause of death. Findings at autopsy included a 100% cellular bone marrow with greater than 95% blasts. Hemorrhages involving the cerebrum, pons, epicardium, lungs, and thymus were present. Prominent leukemic infiltrates and leukostasis were present in the brain, heart, lungs, spleen, hilar lymph nodes, liver, and kidneys. A peripheral blood smear and automated blood cell count showed a white blood cell count of 435 × 10/L with greater than 80% circulating blasts. Immunohistochemical stains confirmed the diagnosis of T lymphoblastic leukemia/lymphoma. Given these circumstances, the diagnosis of acute leukemia should be considered when an intracerebral hemorrhage and/or visceral hemorrhages are identified on internal examination for appropriate collection of tissue for smears and microscopic examination. This case also highlights the uncommon, although serious, risks associated with acute lymphoblastic leukemia and hyperleukocytosis.

FMS-like tyrosine kinase 3 (FLT3) mutation in T lymphoblastic leukemia/lymphoma (T-LL) is rare (∼4%) and reported only in cases with CD117 expression. This study aimed to identify the immunophenotypic features that may predict FLT3 mutations. We report 3 (43%) of 7 CD117(+) T-LL cases harboring FLT3-internal tandem duplication mutation. Compared with 4 FLT3-unmutated cases, all 3 FLT3-mutated cases had a distinct immunophenotype (CD1a(-)/CD2(+)/CD7(+)/CD34(+)/CD117(uniform+)/Tdt(+)) corresponding to the stage of earliest thymic T-cell progenitors possessing myeloid lineage potential. Indeed, all FLT3-mutated T-LL cases expressed myeloperoxidase on a very small subset of blasts and, thus, may be further considered a mixed phenotype acute leukemia, T/myeloid, by the 2008 World Health Organization classification scheme. We conclude that this unique immunophenotype (CD1a(-)/CD2(+)/CD7(+)/CD34(+)/CD117(+)/Tdt(+)) is a better predictor of FLT3 mutation than sole CD117 expression.