Precursor T-cell Lymphoblastic Lymphoma Research Articles

Mechanisms Underlying the Development of Murine T-Cell Lymphoblastic Lymphoma/Leukemia Induced by Total-Body Irradiation.

Exposure to ionizing radiation is associated with an increased risk of hematologic malignancies in myeloid and lymphoid lineages in humans and experimental mice. Given that substantial evidence links radiation exposure with the risk of hematologic malignancies, it is imperative to deeply understand the mechanisms underlying cellular and molecular changes during the latency period between radiation exposure and the emergence of fully transformed malignant cells. One experimental model widely used in the field of radiation and cancer biology to study hematologic malignancies induced by radiation exposure is mouse models of radiation-induced thymic lymphoma. Murine radiation-induced thymic lymphoma is primarily driven by aberrant activation of Notch signaling, which occurs frequently in human precursor T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (T-ALL). Here, we summarize the literature elucidating cell-autonomous and non-cell-autonomous mechanisms underlying cancer initiation, progression, and malignant transformation in the thymus following total-body irradiation (TBI) in mice.

Risk of Central Nervous System Relapse in Patient with Peripheral T-Cell Lymphoma: Absolute Lymphocytes Count and Lymphocytes Percent at Diagnosis As Predictors

BackgroundT-cell lymphoma (TCL) consists of a group of rare and usually aggressive, fast-growing Non-Hodgkin Lymphoma (NHL) that develop from T-cells. Most TCL are Peripheral T-cell lymphoma (PTCL). Central nervous system relapse is a rare but fatal complication of patients with PTCL. Several studies have identified risk factors for CNS relapse in PTCL patients, such as elevated serum lactate dehydrogenase (LDH), >1 extranodal sites of involvement, high International Prognostic Index (IPI) score and specific histological subtypes.AimTo investigate risk factors for CNS relapse in PTCL patients including absolute lymphocytes count (ALC) and lymphcytes percent at time of diagnosis.Methods35 patients diagnosed with PTCL between January 2003 and December 2016 at King Abdullah University Hospital (KAUH) were retrospectively reviewed including: 12 not otherwise specified (NOS), 8 adult T-cell leukemia/lymphoma (ATLL), 7 anaplastic large cell lymphoma (ALCL), 3 angoimmunoblastic T-cell lymphoma (AITL), 3 cutaneous T-cell lymphoma (CTCL) and 2 precursor T-cell lymphoblastic lymphoma (PTLL). Clinical and laboratory data at time of diagnosis including gender, age, presenting symptoms, lactate dehydrogenase level (LDH), hemoglobin level (Hb), complete blood count (CBC), lymphocyte percent, albumin level ,pathological subtypes and CT and PET/CT scans were studied. patients followed-up and CNS relapses was confirmed by cerebrospinal fluid (CSF) analysis or histopathological studies. Patients with CNS involvement at diagnosis were excluded from the study. All patients received the same CHOP treatment regimen. None of our patients received prophylactic intrathecal chemotherapy.The optimal cut-off value for ALC and lymphocytes percent was obtained using the Receiver Operating Curve (ROC) with a determination of the sensitivity and specificity .ResultsAmong 265 patients diagnosed with NHL, only 35 patients (13.21%) confirmed to have PTCL. 24 patients (68.6%) were males and 11 patients (31.4%) were females. 7 patients (20%) had CNS relapse during the follow-up period. Patient characteristics are summarized in the table. There was significant association between CNS involvement and PTCL subtypes (P-value=.021), involvement of more than one extra-nodal site (P-value=.001) and albumin serum level <40 g/L (P-value=.022) too. The mean age (32.86 years) of patients with CNS relapse was significantly lower than the mean age (45.96 years) of patient without CNS relapse (P-value=.048). Median lymphocytes percent was 25% (range , 7.6%-92%) and the optimal cutoff value of lymphocytes % for predicting CNS relapse risk was 30.75 % (Sensitivity 83.3% , Specificity 82.10%; area under the curve [AUC] value: 0.833, 95% confidence interval [CI] 0.637-.994 , P-value = 0.011). In univariate analysis, High lymphocytes percent was significantly associated with CNS relapse (P-value=0.007). Median ALC was 1840 cells/mm3 (range , 340 cells/mm3 -10500 cells/mm3) and the optimal cutoff value of ALC for predicting CNS relapse risk was 2052 cells/mm3 (Sensitivity 83.3% , Specificity 64.3%; area under the curve [AUC] value: 0.798, 95% confidence interval [CI] 0.633-.962, P -value = 0.024). In univariate analysis, ALC higher than 2052 cells/mm3 wasn't significantly associated with CNS relapse (P-value=0.087). In multivariate analysis, CNS relapse was significantly associated with more than one extra-nodal site involvement (P-value=.001), ALC higher than 2052 cells/mm3 (P-value=.033), lymphocytes % higher than 30.75 (P-value=.001) and albumin serum level <40 g/L (P-value=.04). There was no significant association between CNS relapse and IPI score (P-value=.099) , PIT score (P-value= .076) and B-symptoms (P-value=.235).SummaryRisk factors for CNS relapses in patients with PTCL at our medical center include : Adult T-cell lymphoblastic lymphoma (ATLL ) and cutaneous T-cell lymphoma (CTCL) subtypes , more than one extranodal site involvement and low serum albumin level at time of diagnosis. Absolute lymphocyte counts higher than 2052 cells/mm3 and Lymphocyte percent higher than 30.75 % at time of diagnosis can be used to predict CNS relapse risk. Identification of CNS relapse risk factors will help in targeting high-risk patients who will benefit from intrathecal chemotherapy prophylaxis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Young Man with a Mass: Non-Early Precursor T-Cell Lymphoblastic Lymphoma

A Young Man with a Mass: Non-Early Precursor T-Cell Lymphoblastic Lymphoma

Patients over 40 years old with precursor T-cell lymphoblastic lymphoma have different prognostic factors comparing to the youngers

This study aimed to analyze the clinical characteristics and prognostic factors of patients, divided into over 40-year-old group or not, with precursor T-cell lymphoblastic lymphoma (Pre-T-LBL). Based on the retrospective analysis of the clinical data of 59 patients with Pre-T-LBL during the period from December 2010 to December 2015, albumin level, anemia, pleural or pericardial effusion, protocol, therapy response, mediastinal mass, lactate dehydrogenase (LDH), and international prognostic index (IPI) or age-adjusted international prognostic index (aaIPI) were summarized. For patients aged <40 years, factors correlating with poor progression-free survival (PFS) were pleural or pericardial effusion, regimen, albumin level and therapy response. Pleural or pericardial effusion, aaIPI score, regimen, LDH increased, albumin level, therapy response and mediastinal mass were all related with poor overall survival (OS). In the patients aged ≥40 years, only anemia associated with PFS. However, anemia, involvement of bone marrow and therapeutic response were all related with poor OS. In conclusion, the patients with Pre-T-LBL are characterized by a low incidence and bad prognosis. Different prognostic factors can be discovered for patients over 40-year-old with Pre-T-LBL comparing to the youngers. New prognostic evaluation factors should be explored for patients ≥40 years old.

A Huge Anterior Mediastinal Thymoma of an Infant: A Case Report

A seven months old male infant visited Severance Children's Hospital for evaluation of anterior mediastinal mass. With chest computed tomography (CT) image and biopsy, precursor T-cell lymphoblastic lymphoma was suspected but the ultrasonography guided biopsy specimen was insufficient to confirm the disease. Because there was a lifethreatening risk to perform open biopsy to the small infant, we started chemotherapy empirically. The mass decreased, however, the lesion increased again and did not respond to the drugs. Finally we decided to resect the anterior mass with sternostomy and the pathology report finally resulted in thymoma. pISSN 2233-5250 / eISSN 2233-4580 http://dx.doi.org/10.15264/cpho.2015.22.2.167 Clin Pediatr Hematol Oncol 2015;22:167∼170

The Clinical Features and Prognosis of Early T-Cell Precursor Subtype of Lymphoblastic Lymphoma in the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study

Abstract Introduction: Recently, early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) was identified as a subtype of T-cell ALL (T-ALL), with distinctive gene expression and cell marker profiles. Some reports revealed that ETP-ALL was associated with a high risk of remission induction failure and relapse. In precursor T-cell lymphoblastic lymphoma (T-LBL), the clinical features and prognosis of the ETP subtype are not clear yet. In this study, we analyzed the data obtained from patients of advanced stage T-LBL to clarify the prognosis of pediatric T-LBL according to the immunophenotypes, including the ETP subtype of LBL. Patients and methods: From November 2004 to October 2010, 136 children (aged 1–18 years) with newly diagnosed advanced stage LBL (stages III and IV) were eligible for the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 study. We analyzed their immunophenotyping data as well as the ETP subtype. The immunophenotype of T-LBL was classified into pro-T, pre-T, intermediate T, and mature T based on the European Group for the Immunological Characterization of Leukemias (EGIL) classification. The definition of ETP subtype LBL was based on a previous report from the Tokyo Children’s Cancer Study Group (Inukai et al, 2011) using a scoring system consisting of the following 11 markers: CD4, CD8, CD13, CD33, CD34, HLA-DR, CD2, CD3, CD4, CD10, and CD56. Both definitions were based on flow cytometric analysis. Results: In this analysis, 104 (76%) patients were diagnosed with T-LBL. Sufficient data to evaluate the EGIL classification was available for 40 out of 104 patients. The remaining patients could not be classified due to incomplete immunophenotypic data. There were 1, 9, 21, and 9 cases of Pro-T, pre-T, intermediate T, and mature T, respectively. The 3-year event-free survival (EFS) of pro-T/pre-T and intermediate T/mature T was 80.0 ± 12.7% and 76.7 ± 7.7%, respectively (P = 0.7586). For evaluating the ETP subtype of LBL, sufficient data, obtained by using the scoring system with 11 markers, was available for 40 patients. Eight (20%) and 32 (80%) patients were classified as having ETP and non-ETP subtype, respectively. Bone marrow involvement for patients with ETP and non-ETP subtype was observed in 7 (88%) and 11 (34%) cases, respectively (P = 0.014). Central nervous system involvement in patients with ETP and non-ETP subtype was observed in 2 (25%) and 0 cases, respectively (P = 0.036). Thus, stage IV classification was more frequently observed in patients with ETP subtype than in patients with non-ETP subtype (P = 0.014). The 3-year EFS of patients with ETP and non-ETP subtype were 75.0 ± 15.3% and 71.9 ± 8.0%, respectively. There was no significant difference in EFS between patients with ETP and non-ETP subtype (P = 0.8281). Conclusion: For 40 out of 104 T-LBL patients, sufficient data was available to evaluate the immunophenotype for EGIL classification and ETP subtype. There was no significant difference in EFS according to the immunophenotypic subtype of T-LBL. In contrast to T-ALL, ETP subtype in LBL was not statistically related to EFS in this analysis. Disclosures No relevant conflicts of interest to declare.

Precursor T-cell lymphoblastic lymphoma extensively involving the mediastinum, pleura and pericardium: A case report.

Precursor T-cell lymphoblastic lymphoma (T-LBL) is a rare type of malignant lymphoma, with clinical manifestations including diaphragmatic lymph node enlargement, accompanied by local oppression and/or systemic lymphoma symptoms. However, extensive involvement of the mediastinum, pleura and pericardium is rare in T-LBL cases. This is the case report of a T-LBL extensively involving the mediastinum, pleura and pericardium in a 54-year-old woman. The patient complained of anhelation, chest tightness and tiredness for ~3 months. A computed tomography (CT) scan of the chest revealed a diffuse mass of soft tissue density involving the mediastinum, pleura and pericardium. Several thoracocenteses indicated inflammatory changes and cytological examination of the pleural fluid and pleural biopsy under CT guidance identified no heterotypic cells. As 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT imaging revealed a diffused moderate FDG uptake (maximum standard uptake value of 4) by the mediastinum, pleura and cardiac sac, we diagnosed a malignant lymphoma. We subsequently successfully performed needle biopsy under PET/CT guidance according to the PET/CT images and the diagnosis of T-LBL was pathologically confirmed.

Secondary Precursor T-Cell Lymphoblastic Lymphoma Following Precursor B-cell Acute Lymphoblastic Leukemia: A Case Report and Review of the Literature

Although relapse of lymphoma/leukemia is not uncommon, sequential development of a second lymphoma/leukemia of a different cell lineage is rare. We report the case of a 3-year-old girl who initially presented with precursor B-cell acute lymphoblastic leukemia (B-ALL), characterized by a cryptic t(12;21) with associated ETV6/RUNX1 fusion, an 11q (MLL) deletion, and a balanced inv(2)(q31q37). She was successfully treated but five years later developedthymicprecursor T-cell lymphoblastic lymphoma (T-LBL) expressing a completely different phenotypic profile. Fluorescence in situ hybridization testing identified a MLL rearrangement but indicated no ETV6/RUNX1 fusion. Although the marrow was uninvolved, aspirates evaluated by chromosome studies revealed the same inv(2q), suggesting a constitutional abnormality distinct from the somatic alterations associated with her B-ALL and T-LBL. This raisesthe possibilityof a potential tumor suppressor gene or proto-oncogene residing in the region of the inversion breakpoints which could contribute to predisposition to the development of lymphoblastic leukemias/lymphomas. While secondary leukemia may emerge as a therapy-related process and the presence of an MLL rearrangement in the T-LBL represents an interesting abnormality in this regard,athymicpresentation would be exceedingly unusual. To our knowledge, this is the first reported case of B-ALL followed by an apparently genetically unrelatedT-LBL.

FAS system deregulation in T-cell lymphoblastic lymphoma

The acquisition of resistance towards FAS-mediated apoptosis may be required for tumor formation. Tumors from various histological origins exhibit FAS mutations, the most frequent being hematological malignancies. However, data regarding FAS mutations or FAS signaling alterations are still lacking in precursor T-cell lymphoblastic lymphomas (T-LBLs). The available data on acute lymphoblastic leukemia, of precursor origin as well, indicate a low frequency of FAS mutations but often report a serious reduction in FAS-mediated apoptosis as well as chemoresistance, thus suggesting the occurrence of mechanisms able to deregulate the FAS signaling pathway, different from FAS mutation. Our aim at this study was to determine whether FAS-mediated apoptotic signaling is compromised in human T-LBL samples and the mechanisms involved. This study on 26 T-LBL samples confirms that the FAS system is impaired to a wide extent in these tumors, with 57.7% of the cases presenting any alteration of the pathway. A variety of mechanisms seems to be involved in such alteration, in order of frequency the downregulation of FAS, the deregulation of other members of the pathway and the occurrence of mutations at FAS. Considering these results together, it seems plausible to think of a cumulative effect of several alterations in each T-LBL, which in turn may result in FAS/FASLG system deregulation. Since defective FAS signaling may render the T-LBL tumor cells resistant to apoptotic cell death, the correct prognosis, diagnosis and thus the success of anticancer therapy may require such an in-depth knowledge of the complete scenario of FAS-signaling alterations.

First Description Of a t(10;11)(q22;q23)/MLL-TET1 Reciprocal Translocation In a T Lymphoblastic Lymphoma With Subsequent Lineage Switch To Acute Myelomonocytic Myeloid Leukemia

TET1 genomic breakpoints and clinical features of MLL-TET1 rearrangements have been described in 13 acute leukemia cases, 11 in AML, 2 in B cell-precursor ALL. The incidence of this rare translocation was evaluated to 0.3% of MLL rearranged AML cases (5 out of 1590 MLL [Meyer C. Leukemia 2013]). Although those cases are very uncommon, their study can improve our current understanding of leukemogenesis. We report here the first t(10;11) MLL-TET1 positive case of lymphoblastic T lymphoma occurring in a 31 years old male patient, with a subsequent transformation to AML.The patient was referred for a large mediastinal mass and right pleural effusion. Mediastinal and bronchus biopsies led to the diagnosis of a precursor-T cell lymphoblastic lymphoma, expressing CD3, CD5, CD4, CD8, CD10 antigens, without any expression of CD34 or CD79.Molecular analyses of the malignant T-cells showed a clonal TCR gamma-chain gene rearrangement together with HOXA10 overexpression. FISH analysis showed a MLL breakage. The partner gene, TET1, was identified using RP11-9E13 and RP11-314J18 BACs, corresponding to the recurrent translocation t(10;11)(q22;q23). MLL-TET1 fusion transcript was detected (intron 8 of TET1 fused to exon 8 of MLL), as well as its reciprocal transcript.The patient was treated following the (GELA) LL03 protocol, and was considered in complete remission after induction and consolidation phases. Fourteen months after the diagnosis, a bone marrow examination was performed for thrombopenia (6 G/L) which revealed a myelomonocytic acute leukemia with trilineage dysplasia.At this time, The MLL-TET1 fusion transcript as well as HOXA10 overexpression was still present but the TCR rearrangement was not detected. A non-familial donor allogeneic bone marrow transplant was performed in CR after intensive chemotherapy, that was complicated by a grade IV acute graft-versus-host disease. The patient died 54 days after the transplant of bacterial sepsis leading to multi-organ failure.MLL-TET1 fusions have been described in 13 cases in the literature, mainly in AMLs (11/13 cases, mostly AML M4 or M5 cases) and in B-ALLs (2/13 cases). The case reported here presents two interesting features. Firstly, this patient harbors the first MLL-TET1 fusion reported to date in T-ALL, and secondly this case presented a lymphoid to myeloid phenotype switch during the time course of the disease.This strongly suggests that the translocation occurred very early during hematopoietic differentiation, prior to the lymphoid/myeloid commitment. As described for the Ph1 chromosome rearrangement, the t(10;11) translocation may arise in hematopoietic stem cell rather than in committed progenitors. These features are also described in 8p11 stem cell syndrome that involves FGFR1. In both cases, genetic rearrangements arise in myeloid or lymphoid neoplasms with possible subsequent transformation.TET family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and play a key role in active DNA demethylation. TET1 and TET2 are also the key enzymes responsible for the presence of 5hmC in mouse embryonic stem cells (ESCs) (Koh KP., Cell Stem Cell 2011), and TET1 functions to regulate the lineage differentiation potential of ESCs. In addition to its role in DNA demethylation, TET1 interacts physically with NANOG and NANOG/TET1 co-occupy genomic loci of genes associated with both maintenance of pluripotency and lineage commitment in embryonic stem cells (Costa Y., Nature 2013). Taken together, these observations enlighten possible mechanism of the lineage switch observed in this case, and may be a rationale for using demethylating agents in MLL-TET1 neoplasms. Disclosures:No relevant conflicts of interest to declare.

Down-regulation of specific miRNAs enhances the expression of the gene Smoothened and contributes to T-cell lymphoblastic lymphoma development

Inappropriate activation of the GLI/hedgehog (GLI/Hh) signalling occurs in several human cancers, including haematological neoplasms. However, little is known about its relevance in precursor T-cell lymphoblastic lymphomas (T-LBL) development. Moreover, the mechanisms whereby GLI/Hh signalling is activated in haematological malignancies are not fully clear. Here, we show that the gene Smoothened (SMO), the only non-redundant gene of this pathway, is up-regulated in mouse and human T-LBL. Interestingly, down-regulation of micro-RNAs mmu-miR-30a and mmu-miR-141 as well as hsa-miR-193b clearly contributes to enhance the expression of this gene in mouse and human lymphomas and, subsequently, to activate the GLI/Hh signalling. Activation of the GLI/Hh signalling in T-LBL promotes cell survival and proliferation, since inhibition of the pathway using short-hairpin-RNA-mediated SMO knockdown, or cyclopamine as a specific antagonist, significantly reduces these cellular processes. These findings suggest that sustained SMO up-regulation may contribute to T-LBL development and advocate the use of specific SMO inhibitors or microRNAs-based therapies as an attractive possibility to treat an important subset of T-LBL.

Non-Hodgkin Lymphoma in a Patient With Cardiofaciocutaneous Syndrome

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome. Mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) have been identified in patients with CFC syndrome. BRAF mutations are involved in more than 80% of CFC syndrome patients, and we have reported earlier that 2 CFC patients with BRAF mutations developed acute lymphoblastic leukemia. Here we report a boy with CFC syndrome who developed non-Hodgkin lymphoma. At 2 months of age, he developed pneumonia with pleurisy and was diagnosed as having non-Hodgkin lymphoma (precursor T-cell lymphoblastic lymphoma) by cytopathologic examination of the pleural fluid. He was suspected of having Noonan syndrome because of his facial appearance, webbed neck, and cubitus valgus. Precursor T-cell lymphoblastic lymphoma was treated by the TCCSG NHL 94-04 protocol. At 9 years of age, he was clinically reevaluated and diagnosed as having CFC syndrome because of his distinctive facial appearance, multiple nevi, and moderate mental retardation. Sequencing analysis showed a germline p.A246P (c.736G>C) mutation in BRAF reported earlier in CFC syndrome. Molecular diagnosis and careful observation should be considered in children with CFC syndrome.

Unmanipulated Haploidentical Peripheral Blood Stem Cell Transplantation for Precursor T-cell Lymphoblastic Lymphoma Relapsed After Autologous PBSCT

Precursor T-cell lymphoblastic lymphoma (T-LBL) is a clinically aggressive disease, associated with a high subsequent relapse rate. We treated a pediatric patient with T-LBL who relapsed after an autologous peripheral blood stem cell transplantation. Unmanipulated peripheral blood was used as a source for the graft. Hematopoietic engraftment was prompt and the risk of graft-versus-host disease was acceptable. The patient has been in continuous complete remission without chronic graft-versus-host disease for 32 months. Hence, haploidentical peripheral blood stem cell transplantation might be one of the adoptive options for salvage therapy in patients with recurrent or refractory T-LBL, and unmanipulated peripheral blood might be acceptable as a graft.

Severe eosinophilia in a case of giardiasis

Dear Editor, Giardia lamblia is a common intestinal parasite with worldwide distribution. Although primarily presenting with gastrointestinal complaints, the clinical manifestations of giardiasis can be varied. A number of patients are asymptomatic and fever is an uncommon finding.1 The infection is generally not associated with haematological abnormalities and the presence of eosinophilia is most unusual.1,2 An atypical presentation of giardiasis, when associated with rare findings such as eosinophilia can lead to diagnostic predicament or raise false alarms as happened in the case of a previously healthy nine years old boy, who presented in a secondary care hospital at Taxila in Northern Pakistan in April 2009. He had a four-day history of high grade fever and vague abdominal discomfort. There was no history of diarrhoea, constipation, vomiting or any drug intake. Systemic examination was unremarkable. He was admitted to the hospital and given symptomatic treatment pending results of investigations, which included complete blood counts and stool examination. Blood picture showed a total leucocyte count (TLC) of 86.6x109/l with an absolute eosinophil count of 78.2x109/l, while stool examination revealed semi-formed stools containing cysts of Giardia lamblia. The high TLC raised concerns about a myeloproliferative disorder. However, as no immature cells were seen on peripheral blood smear microscopy, it was decided to first treat giardiasis before considering bone marrow examination. The patient was administered oral metronidazole 15 mg/kg/day in three divided doses for seven days. Stool samples were examined on three consecutive days to exclude helminthic infestations. No antihelminthic preparations were given. The patient became afebrile on second day of hospitalization and his eosinophil count dropped to 39.8x109/l on fifth day, when he was discharged with instructions to report back after seven days. On follow-up, he was symptom-free with an absolute eosinophil count of 16.8x109/l on seventh day after discharge and 0.3x109/l three weeks later. Eosinophilia is defined as an absolute eosinophil count of >0.35x109/l in peripheral blood and is considered severe if the count is >5x109/l.3 Severe eosinophilia is associated with a number of conditions including helminthic infections, precursor B-cell acute lymphoblastic leukemia, precursor T-cell lymphoblastic lymphoma and various hypereosinophilic syndromes usually characterized by end-organ involvement.4 A few cases of giardiasis associated with eosinophilia have been reported5–7 but the extremely high eosinophil count seen in our patient is virtually unknown. The unusual presentation of giardiasis in this case could have posed a diagnostic dilemma. Fortunately, the positive stool examination for Giardia lamblia kept us on the right track. The prompt resolution of eosinophilia following treatment of giardiasis with metronidazole appears to confirm a causal relationship with the parasite. A similar reduction of blood eosinophilia following metronidazole therapy in a case of Churg-Strauss syndrome with giardiasis in Italy supports this association.6 However, the pathogenesis of eosinophilia in these cases is not known. The rarity of this finding implies that infection with Giardia lamblia alone is not enough to trigger an eosinophilic response and there must be other factors involved. Dos Santos and Vituri, who reported an association of eosinophilia with giardiasis in a Brazilian study, have suggested the possible role of Giardia lamblia allergens in provoking eosinophilia,7 while Ferrante et al have attributed this finding to an interaction between different eosinophilopoietic stimuli.6 However, these are conjectures and the exact mechanism remains unexplained. Contrary to the general perception that Giardia lamblia only causes gastrointestinal disease and that giardiasis does not lead to haematological changes; it not only presents in a variety of ways without diarrhoea but can also cause reactive eosinophilia in patients with sub-clinical infection. The possibility of giardiasis should be kept in mind while diagnosing a case of unexplained eosinophilia.

Precursor-T Lymphoblastic Lymphoma After Unrelated Bone Marrow Transplantation in a Patient With Fanconi Anemia

Lymphoid malignancies are rare in patients with Fanconi anemia (FA), particularly after bone marrow transplantation. A boy, who was diagnosed with FA at the age of 5; underwent successful bone marrow transplantation at the age of 11. One year later, he presented with fever and dry cough, and was found to have an anterior mediastinal tumor. Biopsy of the tumor revealed precursor-T cell lymphoblastic lymphoma. Human leukocyte antigen analysis confirmed that the tumor cells were derived from the patient's own cells. He received mild chemotherapy for lymphoma, but his condition deteriorated rapidly and he died from excessive chemotherapy-related toxicity. The literature contains no reports of successful chemotherapy for lymphoid tumors in patients with FA, and therefore, alternatives to chemotherapy should be considered in the treatment of such patients.

BIOMED-2 protocols to detect clonal immunoglobulin and T-cell receptor gene rearrangements in B- and T-cell lymphomas in southern Taiwan

Monoclonal expansions of immunoglobulin (Ig) and T-cell receptor (TCR) genes are, respectively, important markers for B- and T-cell malignancies. We used BIOMED-2 protocols to detect clonality of these genes in B- (BCL) and T-cell lymphoma (TCL) in southern Taiwan. Heteroduplex analysis was used after PCR reactions. Ig/TCR clonality rates were 95% (22 in 23 cases) for BCL and 76% (19 in 25 cases) for TCL. These results reveal overall satisfactory detection rates for both BCL and TCL. None of the four natural killer (NK)/T-cell lymphomas detected showed TCR gene clonality, which suggested that BIOMED-2 protocols distinguished the NK/T-cell lymphoma from TCL. In addition, three of the five tested precursor T-cell lymphoblastic lymphomas showed no TCR gene clonality, probably because the immature T-cells in this type of TCL had not undergone TCR gene rearrangements. We conclude that BIOMED-2 protocols are suitable for detecting Ig and TCR clonalities in B- and T-cell malignancies in southern Taiwan.

8p11.2 Translocations: Prevalence, FISH Analysis for FGFR1 and MYST3, and Clinicopathologic Correlates in a Consecutive Cohort of 13 Cases From a Single Institution.

Abstract 1887Poster Board I-910 Background:Chromosomal translocations involving 8p11.2 give rise to diverse oncogenic fusion genes including FGFR1 and MYST3. FGFR1 rearrangements have been associated with the stem cell leukemia/lymphoma (SCLL) syndrome, which is a mixed myeloid-lymphoid malignancy characterized by eosinophilia, monocytosis and rapid disease progression into acute myeloid leukemia or lymphoblastic lymphoma. MYST3 is a histone acetyltransferase whose rearrangement has been associated with acute myeloid leukemia (AML; usually monocytic). Methods:The Mayo Clinic cytogenetic database spanning the years 1988–2009 was screened for 8p11.2 translocations. Bone marrow (BM) pathology and cytogenetic results were re-reviewed and relevant clinical information was retrospectively obtained. Archived BM specimens were analyzed by FISH to identify FGFR1 and/or MYST3 rearrangements. BAC clones used for direct-labeled break-apart FISH probes for FGFR1 were CTC-497A2, RP11-90P5 and RP11-513D5 for the 5' portion and RP11-675F6 and RP11-495O10 for the 3' portion; those used for direct-labeled dual color, dual fusion FISH probes for MYST3 were RP11-589C21, CTD-2532C15, RP11-45I11 and RP11-411A18 and for CREBBP (16p13.3) were RP11-737F1, RP11-136I22, Rp11-962J17 and CTD-2514E9. Results:Out of 24,262 unique patient cytogenetic studies, 8p11.2 translocations were identified in 14 (∼0.06%) patients; 6 constituted sole abnormalities. BM specimens for FISH analysis were available in 13 patients (age range 52–75 years; 8 males). Twelve of these 13 patients had myeloid neoplasms and one had lymphoma; the latter patient had a t(8;10)(p11.2;p13) translocation as a subclone of a 14q32 abnormality and neither FGFR1 nor MYST3 were involved. Among the 12 patients with myeloid neoplasms, FISH analysis revealed abnormalities of MYST3 in 4 patients, FGFR1 in 4 patients, and neither in 4 patients.The MYST3 abnormalities included MYST3-CREBBP in 2 patients, MYST3-EP300 in one patient and MYST3 amplification in one patient; specific diagnoses included AML with or without antecedent chronic myeloid malignancy. Only one of the 4 patients with FGFR1 rearrangements displayed peripheral blood eosinophilia; specific diagnoses included chronic myeloid malignancy and AML. Three of the remaining 4 patients with neither FGFR1 nor MYST3 abnormalities had highly complex cytogenetic abnormalities except one who had sole t(8;13)(p11.2,q12) and presented with lymphadenopathy (precursor-T cell lymphoblastic lymphoma), marked leukocytosis, eosinophilia, monocytosis, and a BM morphology consistent with MPN (marked myeloproliferation with granulocytosis and eosinophilia). Survival was uniformly poor in all 8p11.2 translocations. Conclusions:8p11.2 translocations are rarely encountered in routine clinical practice and are usually associated with aggressive myeloid malignancies. In the current unselected series of patients, peripheral blood eosinophilia was not a typical feature of the myeloid neoplasm phenotype associated with FGFR1 translocation. Conversely, at least by FISH, FGFR1 was not involved in an 8p11.2-associated myeloid neoplasm that exhibited SCLL-like features. Additional molecular studies are planned to validate the current findings. Disclosures:No relevant conflicts of interest to declare.

Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia

Although deletions of cell cycle regulatory gene loci have long been reported in various malignancies, little is known regarding their relevance in pediatric T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (TALL). The current study focused on loss of heterozygosity (LOH) analyses of the CDKN2A/B (chromosome 9p), ATM (chromosome 11q) and p53 (chromosome 17p) gene loci. Frequencies of LOH were compared in 113 pediatric T-LBL and 125 T-ALL who were treated uniformly according to ALL-BFM strategies. Furthermore, LOH findings were correlated with clinical characteristics and tested for their prognostic relevance. LOH at 9p was detected in 47% of T-LBL and 51% of T-ALL, and was associated with male gender in both. In T-ALL, LOH at 9p was associated with favorable initial treatment response. A tendency for favorable event-free-survival was observed in LOH 9p positive T-LBL. The frequency of LOH at chromosomes 11q and 17p was 5% or less for both diseases.

Primary brain T-cell lymphoma of the lymphoblastic type presenting as altered mental status

The authors present a case of a 56-year-old man with altered mental status. Magnetic resonance imaging (MRI) of the brain revealed non-enhancing abnormalities on T2 and FLAIR imaging in the brainstem, cerebellum, and cerebrum. Immunohistochemisty demonstrated precursor T-cell lymphoblastic lymphoma. After treatment with methotrexate, he improved clinically without focal sensorimotor deficits and with improving orientation. MRI showed almost complete resolution of brainstem and cerebral lesions. To the authors’ knowledge, there are only five previous reports of primary central nervous system T-cell lymphoblastic lymphoma. Since treatable, it deserves consideration in patients with altered mental status and imaging abnormalities that include diffuse, non-enhancing changes with increased signal on T2-weighted images.

Poor Outcome for Children and Adolescents With Progressive Disease or Relapse of Lymphoblastic Lymphoma: A Report From the Berlin-Frankfurt-Muenster Group

Little is known about the outcome of pediatric patients with lymphoblastic lymphoma (LBL) who suffer from progressive disease or relapse. We analyzed the pattern of LBL relapses after current non-Hodgkin's lymphoma Berlin-Frankfurt-Muenster (BFM) frontline therapy between April 1990 and March 2003. Relapse therapy was according to acute lymphoblastic leukemia (ALL) -Relapse-BFM protocols or ALL-BFM protocols for high-risk patients. Twenty-eight (11%) of 251 registered patients with precursor T-cell LBL (T-LBL) and six (8%) of 73 patients with precursor B-cell LBL (pB-LBL) suffered from relapse. Of the 28 patients with T-LBL, one died from infection during relapse chemotherapy, 18 failed to achieve stable remission and died from disease progression, and nine reached allogeneic stem-cell transplantation (SCT). Two of these nine patients who underwent SCT died from transplantation-associated toxicity, three died from disease progression, and four are still alive. These four patients are in second remission of their lymphoma for 48, 68, 125, and 131 months, respectively, after allogeneic SCT. One of the four patients developed colon adenocarcinoma 47 months after SCT. Of the six patients with pB-LBL who experienced relapse, one patient died as a result of toxicity of relapse chemotherapy, two died from disease progression after chemotherapy, and three received allogeneic SCT. Of these, two died from subsequent disease progression, and one is still alive 57 months after allogeneic SCT. Using modern conventional therapy in the frontline treatment of LBL, 10% of patients suffer from progressive disease or relapse. Because of the extremely poor reinduction success, the salvage rate for these patients is poor, with only a 14% (SE = 6%) overall survival. Long-term survival was only achieved in those few patients who were able to undergo an allogeneic SCT.