Drug transporters on arachnoid barrier cells contribute to the blood-cerebrospinal fluid barrier.

The subarachnoid space, where cerebrospinal fluid (CSF) flows over the brain and spinal cord, is lined on one side by arachnoid barrier (AB) cells that form part of the blood-CSF barrier. However, despite the fact that drugs are administered into the CSF and CSF drug concentrations are used as a surrogate for brain drug concentration following systemic drug administration, the tight-junctioned AB cells have never been examined for whether they express drug transporters that would influence CSF and central nervous system drug disposition. Hence, we characterized drug transporter expression and function in AB cells. Immunohistochemical analysis showed P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in mouse AB cells but not other meningeal tissue. The Gene Expression Nervous System Atlas (GENSAT) database and the Allen Mouse Brain Atlas confirmed these observations. Microarray analysis of mouse and human arachnoidal tissue revealed expression of many drug transporters and some drug-metabolizing enzymes. Immortalized mouse AB cells express functional P-gp on the apical (dura-facing) membrane and BCRP on both apical and basal (CSF-facing) membranes. Thus, like blood-brain barrier cells and choroid plexus cells, AB cells highly express drug transport proteins and likely contribute to the blood-CSF drug permeation barrier.

Successful treatment of pediatric plasmacytoid dendritic cell tumors with a contemporary regimen for acute lymphoblastic leukemia.

Dendritic cell leukemia (DCL) or hematodermic tumor is an uncommon subtype of acute leukemia. In contrast to adult cases, children tend to have a less aggressive course. The diagnosis of DCL should be considered when its characteristic morphologic features are present and leukemic cells co-express CD4 and CD56. Cases of DCL among pediatric patients have been reported to respond to therapeutic regimens for acute lymphoblastic leukemia, but details regarding the specifics of therapy are lacking.

Treating childhood acute lymphoblastic leukemia without cranial irradiation.

BACKGROUND: Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. METHODS: We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. RESULTS: The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection. CONCLUSIONS: With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.)

A single-arm pilot phase II study of gefitinib and irinotecan in children with newly diagnosed high-risk neuroblastoma.

BACKGROUND: Gefitinib potently inhibits neuroblastoma proliferation in vitro, and the gefitinib/irinotecan combination shows greater than additive activity against neuroblastoma xenografts. This Phase II pilot study estimated the rate of response to two courses of intravenous irinotecan plus oral gefitinib in children with untreated high-risk neuroblastoma. METHODS: Two courses of irinotecan [15 mg/m(2)/day (daily ×5)×2] were combined with 12 daily doses of gefitinib (112.5 mg/m(2)/day). Response was assessed after 6 weeks. A response rate >55% was sought. RESULTS: Of the 23 children enrolled, 19 were evaluable for response. Median age at diagnosis was 3.1 years (range, 18 days-12.7 years). Most patients were older than 24 months (n = 20; 87%), male (n = 18; 78%), white (n = 16; 70%), had INSS 4 disease (n = 19; 83%), and had adrenal primary tumors (n = 18; 78%); nine patients (39%) had amplified tumor MYCN. The toxicity of gefitinib/irinotecan was mild and reversible (nausea, 5/20; diarrhea, 8/20; vomiting, 7/20). Five patients had partial responses; 9 others had a 23%-60% decrease in primary tumor volume and/or improved MIBG scans or decreased bone or bone marrow tumor burden. Median (range) systemic irinotecan exposure (AUC) was 283 ng/ml*hr (range, 163-890 ng/ml*hr) and 28 ng/ml*hr (3.6-297 ng/ml*hr) for the active metabolite, SN-38. No relation was observed between response and tumor expression of EGFR, MRP2-4, ABCG2, and Pgp. CONCLUSIONS: Although the gefitinib/irinotecan combination was very tolerable and induced responses, it was not sufficiently active to warrant further investigation. Initial investigational studies of this type can preclude the necessity for larger, longer, and costlier trials.

CPX-351 induces remission in newly diagnosed pediatric secondary myeloid malignancies.

Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children and adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT), but there has been no innovation in cytoreductive regimens. CP X-351, a fixed 5:1 molar ratio of liposomal cytarabine to daunorubicin, has shown favorable safety and efficacy in elderly individuals with secondary AML and children with relapsed de novo AML. We report the outcomes of 7 young patients (6 with newly diagnosed sMDS/AML and 1 with primary MDS/AML) uniformly treated with CP X-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-cell acute lymphoblastic leukemia; 1 had predisposing genomic instability disorder (Cornelia de Lange syndrome) and 1 had MDS-related AML and multiorgan failure. The median age at diagnosis of myeloid malignancy was 17 years (range, 13-23 years). Patients received 1 to 3 cycles of CP X-351 (cytarabine 100 mg/m2 plus daunorubicin 44 mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding an FLT3 inhibitor as individualized therapy in 1 patient. Six patients were alive and leukemia-free at 0.5 to 3.3 years after HCT. One patient died as a result of disease progression before HCT. To summarize, CP X-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML that warrants prospective studies.

c-Myc is a target of RNA-binding motif protein 15 in the regulation of adult hematopoietic stem cell and megakaryocyte development.

RNA-binding motif protein 15 (RBM15) is involved in the RBM15-megakaryoblastic leukemia 1 fusion in acute megakaryoblastic leukemia. Although Rbm15 has been reported to be required for B-cell differentiation and to inhibit myeloid and megakaryocytic expansion, it is not clear what the normal functions of Rbm15 are in the regulation of hematopoietic stem cell (HSC) and megakaryocyte development. In this study, we report that Rbm15 may function in part through regulation of expression of the proto-oncogene c-Myc. Similar to c-Myc knockout (c-Myc-KO) mice, long-term (LT) HSCs are significantly increased in Rbm15-KO mice due to an apparent LT-HSC to short-term HSC differentiation defect associated with abnormal HSC-niche interactions caused by increased N-cadherin and beta(1) integrin expression on mutant HSCs. Both serial transplantation and competitive reconstitution capabilities of Rbm15-KO LT-HSCs are greatly compromised. Rbm15-KO and c-Myc-KO mice also share related abnormalities in megakaryocyte development, with mutant progenitors producing increased, abnormally small low-ploidy megakaryocytes. Consistent with a possible functional interplay between Rbm15 and c-Myc, the megakaryocyte increase in Rbm15-KO mice could be partially reversed by ectopic c-Myc. Thus, Rbm15 appears to be required for normal HSC-niche interactions, for the ability of HSCs to contribute normally to adult hematopoiesis, and for normal megakaryocyte development; these effects of Rbm15 on hematopoiesis may be mediated at least in part by c-Myc.

Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital.

To characterize the biology and optimal therapy of acute mixed-lineage leukemia in children, we reviewed the pathologic and clinical features, including response to therapy, of 35 patients with mixed-lineage leukemia. The majority of cases (91%) had blasts cells that simultaneously expressed either T-lineage plus myeloid markers (T/myeloid, n = 20) or B-lineage plus myeloid markers (B/myeloid, n = 12). Overall survival rates for the B/myeloid and T/myeloid subgroups were not significantly different from each other or from the rate for acute myeloid leukemia (AML) but were inferior to the outcome in children with acute lymphoblastic leukemia (ALL). Patients who failed to achieve complete remission with AML-directed therapy could often be induced with a regimen of prednisone, vincristine, and L-asparaginase. Analysis of gene-expression patterns identified a subset of biphenotypic leukemias that did not cluster with T-cell ALL, B-progenitor ALL, or AML. We propose that treatment for biphenotypic leukemia begin with one course of AML-type induction therapy, with a provision for a switch to lymphoid-type induction therapy with a glucocorticoid, vincristine, and L-asparaginase if the patient responds poorly. We also suggest that hematopoietic stem cell transplantation is often not required for cure of these patients.

R2* magnetic resonance imaging of the liver in patients with iron overload.

R2* magnetic resonance imaging (R2*-MRI) can quantify hepatic iron content (HIC) by noninvasive means but is not fully investigated. Patients with iron overload completed 1.5T R2*-MRI examination and liver biopsy within 30 days. Forty-three patients (sickle cell anemia, n = 32; beta-thalassemia major, n = 6; and bone marrow failure, n = 5) were analyzed: median age, 14 years, median transfusion duration, 15 months, average (+/-SD) serum ferritin 2718 plus or minus 1994 ng/mL, and average HIC 10.9 plus or minus 6.8 mg Fe/g dry weight liver. Regions of interest were drawn and analyzed by 3 independent reviewers with excellent agreement of their measurements (intraclass correlation coefficient = 0.98). Ferritin and R2*-MRI were weakly but significantly associated (range of correlation coefficients among the 3 reviewers, 0.41-0.48; all P < .01). R2*-MRI was strongly associated with HIC for all 3 reviewers (correlation coefficients, 0.96-0.98; all P < .001). This high correlation confirms prior reports, calibrates R2*-MRI measurements, and suggests its clinical utility for predicting HIC using R2*-MRI. This study was registered at www.clinicaltrials.gov as #NCT00675038.

Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial.

BACKGROUND: We sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment. METHODS: From Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m(2), n=113) or low-dose (2 g/m(2), n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov, number NCT00136084. FINDINGS: Complete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34%vs 42%, p=0.17). The 6-month cumulative incidence of grade 3 or higher infection was 79.3% (SE 4.0) for patients in the high-dose group and 75.5% (4.2) for the low-dose group. 3-year event-free survival and overall survival were 63.0% (SE 4.1) and 71.1% (3.8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0.1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2.41, 95% CI 1.36-4.26; p=0.003) and overall survival (2.11, 1.09-4.11; p=0.028). INTERPRETATION: Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML. FUNDING: National Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC).

Patterns of liver iron accumulation in patients with sickle cell disease and thalassemia with iron overload.

The rate and pattern of iron deposition and accumulation are important determinants of liver damage in chronically transfused patients. To investigate iron distribution patterns at various tissue iron concentrations, effects of chelation on hepatic iron compartmentalization, and differences between patients with sickle cell disease (SCD) and thalassemia major (TM), we prospectively investigated hepatic histologic and biochemical findings in 44 patients with iron overload (35 SCD and 9 TM). The median hepatic iron content (HIC) in patients with TM and SCD was similar at 12.9 and 10.3 mg Fe/g dry weight, respectively (P = 0.73), but patients with SCD had significantly less hepatic fibrosis and inflammation (P < 0.05), less hepatic injury, and significantly less blood exposure. Patients with SCD had predominantly sinusoidal iron deposition, but hepatocyte iron deposition was observed even at low HIC. Chelated patients had more hepatocyte and portal tract iron than non-chelated ones, but similar sinusoidal iron deposition. These data suggest that iron deposition in patients with SCD generally follows the traditional pattern of transfusional iron overload; however, parenchymal hepatocyte deposition also occurs early and chelation removes iron preferentially from the reticuloendothelium. Pathophysiological and genetic differences affecting iron deposition and accumulation in SCD and TM warrants further investigation.

Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.

BACKGROUND: About a fifth of children with acute T-lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome. METHODS: Leukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL. FINDINGS: 30 patients (12.6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a(-), CD8(-), CD5(weak) with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40-100] at 10 years vs 10% [4-16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25-89] at 2 years vs 14% [6-22] at 2 years for patients treated in the AIEOP trial). INTERPRETATION: ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy. FUNDING: US National Cancer Institute, Cariplo Foundation, Citta della Speranza Foundation, Italian Association for Cancer Research (AIRC), Italian Ministry for University and Research, and American Lebanese Syrian Associated Charities (ALSAC).

Prognostic significance of myeloperoxidase expression in childhood acute myeloid leukemia.

BACKGROUND: The percentage of myeloperoxidase (MPO)-positive blast cells is associated with prognosis in adult acute myeloid leukemia (AML), but this association is unsubstantiated in pediatric AML. PROCEDURE: We retrospectively compared cytochemical MPO results with outcome in 154 patients younger than 21 years treated on three consecutive institutional protocols for newly diagnosed AML (1987-2001). Patients with FAB M0 and M7 AML (no MPO expression) or M3 AML (100% MPO expression) and Down's syndrome were excluded. RESULTS: Median MPO expression was higher in FAB M2 subtype than in other subtypes (P < 0.0001) and differed significantly across cytogenetic risk groups (P = 0.002) with highest MPO expression among those with favorable karyotypes. The percentage of MPO-positive blasts was not significantly associated with the probability of complete remission (P = 0.97), event-free survival (P = 0.72), or survival (P = 0.76) in multivariate analyses that accounted for age, FAB subtype, presenting WBC count, cytogenetic and protocol treatment risk group. In analysis limited to patients with intermediate-risk cytogenetics, higher MPO expression appeared to be associated with improved EFS (P = 0.06) but was not associated with remission induction rate (P = 0.16) or overall survival (P = 0.38). CONCLUSIONS: The percentage of MPO-positive blast cells is related to FAB subtype in pediatric AML but has limited prognostic relevance.

Conjunctival posttransplantation lymphoproliferative disorder.

PURPOSE: To describe a patient with conjunctival posttransplantation lymphoproliferative disorder (PTLD). DESIGN: Interventional case report. METHODS: A 8-year-old boy, three months status post bone marrow transplantation with bilateral enlarged gelatinous bulbar conjunctiva was examined. Biopsy of the bulbar conjunctiva was performed. RESULTS: Conjunctival biopsy revealed a polymorphous infiltrate of lymphoid cells with large atypical immunoblastic lymphoma cells, plasmacytoid lymphocytes, and plasma cells. B-cell markers CD20 and CD79a were positive. Plasma cells exhibited restriction for kappa immunoglobulin light chain and were positive for CD79a. Most cells were positive for Epstein-Barr virus (EBV) encoded ribonucleic acid. EBV-related polymorphic PTLD was diagnosed and treated with discontinuation of cyclosporine, reduction in prednisone dosage and administration of EBV-specific cytotoxic T lymphocytes. The conjunctival lesions resolved during the next five weeks. CONCLUSIONS: Posttransplantation lymphoproliferative disorder rarely involves the ocular structures with most cases presenting as a masquerade syndrome. This case illustrates that PTLD can involve the conjunctiva and further expands the clinical spectrum of ocular PTLD.

Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia.

CONTEXT: Little is known about the incidence of secondary neoplasms after 15 to 20 years in children and adolescents who were treated for acute lymphoblastic leukemia. OBJECTIVES: To investigate the cumulative incidence of secondary neoplasms in pediatric patients treated for acute lymphoblastic leukemia over 30 years and to characterize late-occurring tumors. DESIGN, SETTING, AND PATIENTS: Retrospective study of 2169 patients with acute lymphoblastic leukemia treated between 1962 and 1998 at St Jude Children's Research Hospital, Memphis, Tenn, who achieved complete remission and had a median follow-up time of 18.7 years (range, 2.4-41.3 years). MAIN OUTCOME MEASURES: Cumulative incidences of secondary neoplasms in first remission and standard incidence ratios of observed rates compared with rates of cancer development in the general US population. RESULTS: Secondary neoplasms developed as the first event in 123 patients and comprised 46 myeloid malignancies, 3 lymphomas, 14 basal cell carcinomas, 16 other carcinomas, 6 sarcomas, 16 meningiomas, and 22 other brain tumors. The cumulative incidence of secondary neoplasm was 4.17% (SE, 0.46%) at 15 years and increased substantially after 20 years, reaching 10.85% (SE, 1.27%) at 30 years. When meningiomas and basal cell carcinomas were excluded, the overall cumulative incidence was 3.99% (SE, 0.44%) at 15 years and 6.27% (SE, 0.83%) at 30 years, representing a 13.5-fold increase in overall risk compared with the general population. The cumulative incidence of each tumor type at 30 years was 2.19% (SE, 0.32%) for myeloid malignancy, 0.17% (SE, 0.10%) for lymphoma, 3.00% (SE, 0.59%) for brain tumor, 4.91% (SE, 1.04%) for carcinoma, and 0.57% (SE, 0.37%) for sarcoma. CONCLUSIONS: The cumulative incidence of secondary neoplasms increases steadily over 30 years after treatment of acute lymphoblastic leukemia. Although the majority of the late-occurring secondary neoplasms are low-grade tumors, the increase in incidence of more aggressive malignant neoplasms is significantly higher than expected in the general population. These results suggest that lifelong follow-up of acute lymphoblastic leukemia survivors is needed to ascertain the full impact of treatment and other leukemia-related factors on secondary neoplasm development.

Histiocytic proliferations in childhood.

Histiocytic disorders occur with increased frequency in children and young adults. The wide spectrum of neoplastic and nonneoplastic diseases characterized by histiocytic proliferation was reflected in the cases submitted to the 2003 Society for Hematopathology and the European Association for Haematopathology Workshop. This review focuses on the entities represented at the workshop. It includes an overview of the classification and immunophenotype of the histiocytic disorders. The clinical and pathologic features of each entity are illustrated with representative cases submitted to the workshop, with an emphasis on recent biologic and genetic insights. In addition, a brief review of the pathologic features of the lysosomal storage disorders is included, with an emphasis on findings relevant to the practicing hematopathologist, exemplified with cases presented at the workshop.

Terminal deoxynucleotidyl transferase-positive lymphoid cells in reactive lymph nodes from children with malignant tumors: incidence, distribution pattern, and immunophenotype in 26 patients.

The presence of terminal deoxynucleotidyl transferase (TdT)-positive lymphoid precursors in benign lymph nodes from children has been characterized insufficiently. By using single- and double-labeling immunohistochemical analysis, we examined the frequency, distribution, morphologic features, and immunophenotype of TdT-positive cells in benign lymph nodes from 26 consecutive pediatric patients (4 boys, 22 girls; age, 10 weeks-17 years; median, 4.5 years), 23 of whom had a history of malignant neoplasm. We identified TdT-positive lymphoid cells in all 26 cases. These cells were found adjacent to medullary and cortical sinuses, with a frequency of 1 to 180 cells per high-powerfield (median, 20 cells), and were present singly and in small clusters. They were morphologically heterogeneous and showed a precursor B-cell immunophenotype including colocalization with CD34 by single-antibody immunohistochemical analysis and coexpression of variable levels of CD79a and CD10 and lack of CD3 expression by double immunostaining. These features should aid in the evaluation of pediatric lymph nodes for partial involvement by lymphoblastic lymphoma/leukemia.

Discrepancies in the immunophenotype of lymphoma cells in samples obtained simultaneously from different anatomic sites.

Few studies have compared the immunophenotypic profiles of non-Hodgkin lymphoma (NHL) cells obtained simultaneously from different anatomic sites. In the present study, we compared flow cytometry immunophenotypic results in 64 consecutive NHL cases in which aspiration or biopsy of 2 sites was performed within 30 days to assess the potential discrepancy rate. In 14 cases (22%), discordant antigen expression was identified, including 4 (36%) of 11 cases with discordant morphologic features and 10 (19%) of 53 cases with concordant morphologic features in the 2 samples. Discrepancies involved 1 antigen in 10 patients and 2 antigens in 4 patients. Antigens most frequently discrepant included CD5 (n = 4), FMC7 (n = 3), and CD20 (n = 3). We conclude that the immunophenotype of NHL cells is generally stable, yet discrepancies can occur in a subset of patients. Differences in immunophenotype may relate to mechanisms of disease dissemination, influence of the microenvironment, or differential response to therapy.

Precursor T-cell acute lymphoblastic leukemia in adults: age-related immunophenotypic, cytogenetic, and molecular subsets.

We analyzed the clinicopathologic and molecular findings in 26 adults (age 16-72 years) with T-cell acute lymphoblastic leukemia (T-ALL) and observed features that correlated with age. Patients older than 60 years (n = 5) had a low frequency of hepatosplenomegaly (0 [0%]), anterior mediastinal mass (1 [20%]), and lymphadenopathy (2 [40%]), and completely responded to chemotherapy (4 of 4). The T-ALL in this group commonly expressed myeloid antigens (4 [80%]), had lineage-inappropriate gene rearrangements (2/3 [67%]) and chromosome 2 deletion (3/4 [75%]), and exclusively used the V(III) or V(IV) families of the T-cell receptor (TCR) gamma gene. In comparison, patients 16 to 60 years old (n = 21) more commonly had an anterior mediastinal mass (8 [38%]), hepatosplenomegaly (10 [48%]), and lymphadenopathy (16 [76%]). The tumors in these patients commonly used the TCR gamma gene VI or V(II) families (17/25 total rearrangements [68%]). Myeloid antigen expression (5 [24%]) and lineage inappropriate gene rearrangements (4/15 [27%]) were uncommon. Within this group, CD1a expression correlated with age 28 to 60 years. These results illustrate considerable age-related heterogeneity in adult T-ALL, which may reflect differences in tumor cell maturation.

Acute lymphoblastic leukemia in elderly patients the Philadelphia chromosome may not be a significant adverse prognostic factor.

Acute lymphoblastic leukemia (ALL) in elderly patients (59 years or older) carries a poor prognosis, and this finding may be attributed to the relatively high frequency of the Philadelphia chromosome (Ph). To test this hypothesis, we reviewed the clinicopathologic features of 23 consecutive, newly diagnosed elderly patients with ALL (14 men, 9 women, aged 59-92 years) uniformly treated at our institution and compared the Ph+ and Ph- groups. Conventional cytogenetic data were available for 21 of 23 cases; 7 (33%) were Ph+. All Ph+ cases were of precursor B-cell type. The remaining 16 tumors were of precursor B-cell (10), mature B-cell (2), precursor T-cell (3), and mixed precursor T-cell/B-cell (1) type. Ph+ and Ph- groups did not differ significantly in median survival (13.4 months vs 19.0 months) or other variables studied. The Ph may not be a significant adverse prognostic factor in ALL in elderly patients.