Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical outcome. Currently 50% of PTCL cases are not classifiable: PTCL-not otherwise specified (NOS). Gene-expression profiles on 372 PTCL cases were analyzed and robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including 114 angioimmunoblastic T-cell lymphoma (AITL), 31 anaplastic lymphoma kinase (ALK)-positive and 48 ALK-negative anaplastic large cell lymphoma, 14 adult T-cell leukemia/lymphoma and 44 extranodal NK/T-cell lymphoma that were further separated into NK-cell and gdT-cell lymphomas. Thirty-seven percent of morphologically diagnosed PTCL-NOS cases were reclassified into other specific subtypes by molecular signatures. Reexamination, immunohistochemistry, and IDH2 mutation analysis in reclassified cases supported the validity of the reclassification. Two major molecular subgroups can be identified in the remaining PTCL-NOS cases characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121). The GATA3 subgroup was significantly associated with poor overall survival (P = .01). High expression of cytotoxic gene-signature within the TBX21 subgroup also showed poor clinical outcome (P = .05). In AITL, high expression of several signatures associated with the tumor microenvironment was significantly associated with outcome. A combined prognostic score was predictive of survival in an independent cohort (P = .004).

MRI of cardiac iron overload.

Transfusion therapy has greatly improved the survival of transfusion dependent thalassemia major (TM) patients; however, the resultant iron load damages tissues including the heart, liver and endocrine organs. Among these, heart complication still remains the leading cause of mortality. Myocardial iron deposition can occur independently of other solid organ involvement; conversely, the heart may be spared despite heavy siderosis in other tissues. Iron chelation treatment diminishes the risk of hemosiderosis; however, the chelation treatment has its own toxicities and might not be available to all patients due to costs. Close monitoring of individual organ iron concentration and function is thus important for optimization of individual patient care. This review outlines the importance and clinical significance of recently available MRI techniques for monitoring cardiac iron load.

The prognostic significance of lymphopenia in peripheral T-cell and natural killer/T-cell lymphomas: a study of 826 cases from the International Peripheral T-cell Lymphoma Project.

Lymphopenia is a marker of inferior survival in patients with various malignancies. However, the prognostic significance of lymphopenia in peripheral T-cell lymphoma (PTCL) is unclear. We analyzed the prognostic significance of lymphopenia in 826 patients with different types of PTCL and natural killer/T-cell lymphoma (NKTCL) from the International Peripheral T-cell Lymphoma Project. Lymphopenia was defined as an absolute lymphocyte count of less than 1,000 cells per microliter. The overall frequency of lymphopenia was 35.3%, ranging from 21.1% in ALK(+) anaplastic large cell lymphoma (ALCL) to 47.5% in angioimmunoblastic T-cell lymphoma (AITL). Lymphopenia was independently associated with an inferior overall survival (OS) in patients with the lymphoma type of adult T-cell leukemia/lymphoma (ATLL), with a 2-year OS of 15% versus 40% for those without lymphopenia (P < 0.001). Lymphopenia was also an adverse predictor of survival in PTCL, not otherwise specified, but was associated with other unfavorable prognostic factors. A trend toward inferior survival for lymphopenic patients was also observed in AITL, ALK(-) ALCL and extranasal NKTCL lymphoma, whereas no difference in survival was found in nasal NKTCL, ALK(+) ALCL, or enteropathy-associated T-cell lymphoma. In this study, lymphopenia was identified as a new adverse prognostic factor in the lymphoma type of ATLL.

Oral arsenic trioxide for relapsed acute promyelocytic leukemia in pediatric patients.

Four patients (age 3-11 years at diagnosis) with relapsed acute promyelocytic leukemia (APL), 12-38 months from diagnosis, were treated with oral arsenic trioxide (As(2) O(3) ). One patient was treated with oral As(2) O(3) monotherapy and chemotherapy. Three patients failed initial oral or intravenous As(2) O(3) monotherapy were treated with oral As(2) O(3) plus ATRA followed by long-term oral maintenance (cumulative As(2) O(3) dose 280-2,100 mg). All patients achieved molecular remission, at a median follow up of 122 (10-132) months with no adverse effects. Oral As(2) O(3) , particularly in prolonged maintenance with oral ATRA may obviate the need of stem cell transplantation in relapsed pediatric APL.

Lower incidence of plasma cell neoplasm is maintained in migrant Chinese to British Columbia: findings from a 30-year survey.

The etiology of plasma cell myeloma (PCM) is largely unknown. Its incidence varies widely in different ethnic groups. Migrant study may help determine the relative contributions of genetic versus environmental factors to PCM pathogenesis. We performed a retrospective review of the computerized records of all patients diagnosed with PCM between 1975 and 2004 in British Columbia (BC), and identified patients of Chinese ethnicity. This was compared with PCM incidence in Hong Kong (HK) Chinese. Age distributions of HK, BC and BC Chinese populations were obtained from the census departments to calculate world age-standardized rates (WASRs). The WASR of PCM over the 30-year period in BC Chinese was 1.64/100 000 person-years (95% confidence interval [CI] 1.37-1.93). This was similar to the WASR observed in HK (1.78, 95% CI 1.73-1.83), with a standardized incidence ratio (SIR) of 0.91 (95% CI 0.74-1.10). The rate was much lower than that in the BC non-Chinese background population (WASR 3.59, 95% CI 3.50-3.68; SIR 0.46, 95% CI 0.38-0.56). The lower rates in BC Chinese were maintained across all years, both genders and in all age groups above 45 years. Our observations suggest a strong genetic component as the cause of differences in the ethnic predisposition to PCM.

Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project.

Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)-cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.

Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project.

The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P < .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (≥ 10 cm), thrombocytopenia (< 150 × 10(9)/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies.

International reproducibility of single breathhold T2* MR for cardiac and liver iron assessment among five thalassemia centers.

PURPOSE: To examine the reproducibility of the single breathhold T2* technique from different scanners, after installation of standard methodology in five international centers. MATERIALS AND METHODS: Up to 10 patients from each center were scanned twice locally for local interstudy reproducibility of heart and liver T2*, and then flown to a central MR facility to be rescanned on a reference scanner for intercenter reproducibility. Interobserver reproducibility for all scans was also assessed. RESULTS: Of the 49 patients scanned, the intercenter reproducibility for T2* was 5.9% for the heart and 5.8% for the liver. Local interstudy reproducibility for T2* was 7.4% for the heart and 4.6% for the liver. Interobserver reproducibility for T2* was 5.4% for the heart and 4.4% for the liver. CONCLUSION: These data indicate that T2* MR may be developed into a widespread test for tissue siderosis providing that well-defined and approved imaging and analysis techniques are used.

Current management of nasal NK/T-cell lymphoma.

Nasal natural killer (NK)/T-cell lymphoma--classified as extranodal NK/T-cell lymphoma (ENKTL), nasal type, by the World Health Organization--is a non-Hodgkin lymphoma that is almost always associated with Epstein-Barr virus. Up to 75% of ENKTL cases occur in the upper aerodigestive tract, primarily the nasal cavity. It is the most common type of peripheral T-cell lymphoma in many Asian countries. Histologic diagnosis is essential, and staging consists of bilateral bone marrow biopsy and imaging of the neck, thorax, abdomen, and pelvis. There is a marked dichotomy in treatment and survival between localized and disseminated disease. Since disease incidence is rare even in prevalent areas, experience is limited and most treatment protocols are consensus-guided. ENKTL is both chemosensitive and radiosensitive. Early-stage, localized nasal disease is highly curable with combination therapy, but the optimal dose, combination, and sequence of radiotherapy and chemotherapy are still undefined. For patients with disseminated and extranasal disease, either at initial presentation or at relapse, the prognosis is poor. For disseminated and refractory cases, the 5-year survival rate is below 10%, and better methods of treatment are needed.

Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is often challenging to diagnose and classify. Gene expression profiling was performed on 144 cases of PTCL and natural killer cell lymphoma and robust molecular classifiers were constructed for angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large-cell lymphoma (ALCL), and adult T-cell leukemia/lymphoma. PTCL-unclassifiable was molecularly heterogeneous, but we were able to identify a molecular subgroup with features of cytotoxic T lymphocytes and a poor survival compared with the remaining PTCL-not otherwise specified cases. Many of the pathologic features and substantial components of the molecular signature of AITL are contributed by the follicular dendritic cells, B-cell, and other stromal components. The expression of Th17-associated molecules in ALK(+) ALCL was noted and may represent aberrant activation of Th17-cell differentiation by abnormal cytokine secretion. Adult T-cell leukemia/lymphoma has a homogeneous molecular signature demonstrating high expression of human T-lymphotropic virus type 1-induced genes. These classifiers reflect the biology of the tumor cells as well as their microenvironment. We also constructed a molecular prognosticator for AITL that appears to be largely related to the microenvironmental signature, and the high expression of 2 immunosuppressive signatures are associated with poor outcome. Oncogenic pathways and tumor-host interactions also were identified, and these findings may lead to better therapies and outcome in the future.

A unique case of B cell lymphoma relapsing as CD4/CD56 blastic neoplasm.

A patient with history of B cell lymphoma treated with rituximab-based chemotherapy relapsed with a blastic CD4+/CD56+ neoplasm that was negative for CD20, CD79a and CD3. The relapse morphology and immunophenotyping were unusual and plasmacytoid dendritic cell (PDC) tumor enters the differential diagnosis. However, expressions of Oct-2 and CD10 in the relapse tumor were both more compatible with B cell than PDC lineage. Molecular investigations showed clonal rearrangements for both immunoglobulin heavy chain (IgH) and T cell receptor (TCR) gamma chain gene by polymerase chain reaction (PCR). Furthermore, a clonal relationship with the original B cell lymphoma was demonstrated for all PCR products. Our case illustrated the potential pitfalls and ambiguity of lineage classification based on morphology and immunophenotyping alone, especially for rare and poorly defined entities.

Chronic myeloid leukemia in Asia.

Chronic myeloid leukemia (CML) in Asia has an incidence rather lower than in Western countries yet tends to afflict a younger population. As in the West, imatinib mesylate (IM, Glivec) has supplanted busulphan, hydroxyurea and interferon-alpha as first-line treatment. Its use has resulted in a dramatic decline in the number of hematopoietic stem cell transplantations (HSCT) performed. Although it is expensive, IM induces a complete cytogenetic response in 60-90% of newly diagnosed patients, and up to 10% for those in blastic phase. The standard dose of 400 mg is well tolerated by most patients, although adverse events have been observed, including drug-induced cytopenia. Through the Glivec International Patient Assistance Program, the majority of CML patients has access to IM and can expect prolonged survival, even in the absence of HSCT. However, just as in Western countries, resistance to imatinib has emerged in Asian countries. They will require the novel tyrosine kinase inhibitors (dasatinib, nilotinib) becoming available through either clinical trials or market approval. This review examines the available data on CML in China, Hong Kong, India, the Philippines, Singapore, South Korea, Taiwan and Thailand.

Isolated gingival relapse of acute lymphoblastic leukemia after transplantation.

A patient with a history of precursor B-cell leukemia presented with an isolated ulcerating gum lesion 8 years after allogeneic stem cell transplantation with severe graft versus host disease. A biopsy revealed an undifferentiated malignant hemic lesion. Examinations of the peripheral blood and marrow were normal. Molecular studies confirmed clonal relationship between the gum lesion with the original marrow disease, despite the anatomical, histological and chronological separations.