Stefanos I. Papadhimitriou

Acute lymphoplasmacytoid dendritic cell (DC2) leukemia: Results from the Hellenic Dendritic Cell Leukemia Study Group

We present a cohort of 22 patients with type 2 dendritic cell (DC2) acute leukemia (or blastic plasmacytoid dendritic cell neoplasm-BPDCN, as it has been recently named), diagnosed in Greece over the past 12-year period, according to the main clinical and immunophenotypic features of this entity. Four additional cases are discussed, classified as leukemia of ambiguous lineage (LAL), because of the simultaneous detection of a CD56 negative DC2 population and of a second myeloid precursor cell population. The morphological features and cytogenetic findings of the typical BPDCN cases were similar to those previously described. Acute lymphoblastic leukemia-type chemotherapeutic regimens were more efficient in controlling the disease. Immunophenotyping of typical BPDCN cases revealed CD4(+), CD56(+), HLA-DR(+) and CD123(bright) neoplastic cells, in the absence of major B-, T- and myeloid-associated markers, while the phenotype of the four cases characterized as LAL highlights the risk of misdiagnosis. Based on our experience, we propose a flow cytometric algorithmic approach for the distinction of typical BPDCN from certain types of acute myeloid leukemia, but also for the identification of acute myeloid leukemia, admixed with CD56 negative DC2 cells, which could be misdiagnosed as BPDCN.

Report of an HIV and HHV-8 negative case of primary effusion lymphoma with idiopathic T4 lymphocytopenia

Although primary effusion lymphoma (PEL) is usually associated with human herpes virus-8/Kaposi sarcoma herpes virus (HHV-8/KSHV) and human immunodeficiency virus (HIV), there are several reports of HHV-8/KSHV and HIV negative cases, mainly in the setting of immunodeficiency. Here, we report the second case of PEL associated with idiopathic T4 lymphocytopenia (ICL), which was HHV-8/KSHV negative, HIV negative and Epstein-Barr virus positive, while no other causative agents for immunodeficiency were documented. Flow cytometry revealed a hyperdiploid and highly mitotic large B-cell population, CD30, EMA, CD66, CD38 and CD71 positive. The malignant lymphoma cells showed atypia with prominent nuclei and basophilic vacuolated cytoplasm, while cytogenetic analysis with fluorescent in situ hybridization showed trisomy 18. The patient was administered R-COP chemotherapy, but no remission was achieved, up to 3 months from diagnosis.

T-cell acute lymphoblastic leukemia relapsing as acute myelogenous leukemia

We present the unusual case of a 16‐year‐old girl with T‐cell acute lymphoblastic leukemia (ALL) with an early thymocyte immunophenotype without myeloid markers, who after 13 months of complete hematological remission relapsed as acute myelogenous leukemia (AML) with minimal differentiation and died of her disease. Whether the AML represented a relapse with lineage switch of the original immature T‐cell clone or a new secondary malignancy, could not be proven due to the absence of molecular or clonal markers. This report suggests that a subset of CD7+ T‐cell leukemias without mature T‐cell antigens (CD4‐, CD8‐) are minimally differentiated and can relapse as AML. Pediatr Blood Cancer 2007;48:354–357.

Immunophenotypic analysis reveals heterogeneity and common biologic aspects in monoclonal B-cell lymphocytosis

Monoclonal B‐cell lymphocytosis (MBL) is the presence of small B‐cell clones in the peripheral blood of healthy subjects. Most MBL have the characteristic phenotype of chronic lymphocyte leukemia (chronic lymphocytic leukemia (CLL)‐like MBL), and depending on the number of monoclonal B‐cells, may characterize a preclinical stage of the CLL. However, there are also MBL with an atypical (CD5+CD20+/brightCD23dim/−) or a CD5neg phenotype, which remain largely unexplored. We performed an extended immunophenotypic, cytogenetic, and hematologic analysis in 75 CLL‐like, 39 atypical, 50 CD5neg, and 7 biphenotypic MBL cases to detect differences or similarities among the MBL subsets. The phenotypic analysis showed expression variations in many surface markers and a wide spectrum of disease‐specific phenotypes within each MBL subtype. Interphase fluorescent in situ hybridization analysis showed a different panel of aberrations according to the phenotype. Overall, del(13q14) and +12 were the most common abnormalities (39%), whereas del(11q13), del(17p13), and del(6q23) were detected only in 3, 1, and 0 cases, respectively. A comparison of MBL with overt chronic lymphoproliferations revealed common aspects in the preclinical state, regarding both the kind of cytogenetic aberrations detected and the lymphocyte composition. Our findings highlight not only the heterogeneity among MBL subsets but also indicate common biologic features which differentiate MBL from clinical disease.

An extended fluorescence in situ hybridization approach for the cytogenetic study of cholangiocarcinoma on endoscopic retrograde cholangiopancreatography brushing cytology preparations.

The cytological diagnosis of cholangiocarcinoma has been significantly aided by applying a 4-probe fluorescence in situ hybridization system on endoscopic retrograde cholangiopancreatography brushing smears, aiming mainly at the detection of hyperdiploidy. However, this approach adds little to our understanding of the genetic background of the disease. With the prospect of obtaining additional data on chromosomal aberrations, we have extended the fluorescence in situ hybridization study, with the application of 4 independent 2-probe systems in 35 patients with documented cholangiocarcinoma. Fluorescence in situ hybridization assays were performed on endoscopic retrograde cholangiopancreatography brushing smears, with probes for the 7q31, 11q13 (CCND1), 17p53 (TP53), and 9p21 (INK4 locus) bands, together with the respective centromeric probe. Hyperdiploidy, involving at least 2 of the 4 chromosomes targeted, was found in 31 patients. 17p13 deletion was detected in 3, and 9p21 deletion, in 5 of the hyperdiploid cases, with the 2 aberrations concurrent in 1. CCND1 amplification was found in 1 case as the sole abnormality and in another together with hyperdiploidy, but in apparently unrelated clones. This work indicates that interphase fluorescence in situ hybridization is a practical and useful tool for the cytogenetic study of cholangiocarcinoma on endoscopic retrograde cholangiopancreatography brushing smears, which is often the only available tissue specimen of the tumor. Apart from hyperdiploidy, it provides additional data on the genetic profile of cholangiocarcinoma, especially regarding structural chromosomal aberrations and clonal diversity. This line of investigation may prove useful in the delineation of oncogenesis and the interpretation of the diverse clinical features of the disease.

Spinal cord compression in an adolescent with relapsed B-precursor acute lymphoblastic leukemia and mental neuropathy

The authors report a case of intraspinal mass associated with recurrence of B-precursor acute lymphoblastic leukemia in an adolescent male who presented with numb chin syndrome at initial diagnosis of the leukemia. The patient developed sensory changes, later on motor weakness, and eventually paraplegia. An emergent MRI scan showed an intraspinal mass at the level of T9 vertebra. Biopsy obtained during laminectomy revealed a mass composed of lymphoblasts immunophenotypically identical to the patient’s known leukemia. Surgical decompression and dexamethasone were ineffective in restoration of the neurological deficits. Intraspinal extramedullary relapses should be considered in the differential diagnosis of leukemic patients with neurological symptoms.

High frequency of human leukocyte antigen class II DRB1*1602 haplotype in Greek patients with myelodysplastic syndrome and of DRB1*1501 in the low-risk subgroup

Myelodysplastic syndromes (MDS) comprise a heterogenous group of clonal hematopoietic disorders in which the immune-mediated pathogenetic mechanisms are under investigation. Overrepresentation of human leukocyte antigen (HLA)-DR2 and its serologic split HLA-DR15 has been associated with low-risk MDS in certain ethnic groups and has been proposed as a predictive factor for a favorable response to immunomodulatory treatment. Because the HLA-DRB1*15 haplotype does not predominate in the Greek population, we investigated the frequency of HLA-DRB1 alleles among 114 patients of Greek origin suffering from various types of MDS: 36 refractory anemia (RA), 24 refractory anemia with ringed sideroblasts (RARS), 19 refractory anemia with excess of blasts (RAEB), 14 refractory anemia with excess of blasts in transformation (RAEB-t), 14 chronic myelomonocytic leukemia, and 7 hypoplastic MDS patients. HLA-DRB1 molecular typing was performed with polymerase chain reaction-sequence specific oligonucleotides and results were compared with that from a previously reported control Greek population. HLA-DRB1*1602 was the only allele that was significantly overrepresented in Greek MDS patients as a whole, whereas HLA-DRB1*1501 allele frequency was significantly higher in Greek patients with low-risk myelodysplasia. Our results suggest the possible value of HLA-DR15 and HLA-DR16 as determinants for immunomodulatory interventions, at least for Greek patients with low-risk MDS.

Chronic Myeloid Leukemia (CML) in Children: Classical and Newer Therapeutic Approaches

Chronic myeloid leukemia (CML) represents a rare myeloproliferative disease among children where allogeneic stem cell transplantation (SCT) remains the curative gold standard. However, the impressive early cytogenetic and molecular responses achieved by tyrosine kinase inhibitors [TKIs (imatinib, nilotinib, and dasatinib)] as first-line or even sole treatment in adults, has led to their increasing use also among children. Due to limited data regarding long-term results of TKIs and especially those of second generation in pediatric cohorts, we would like to add clinical information in this rare series of patients by reporting on four children with CML over a 10-year period, focusing on TKIs, dose escalations and clinical responses.

TEL/AML1+ ACUTE LYMPHOBLASTIC LEUKEMIA IN THE GREEK PEDIATRIC POPULATION

INTRODUCTION: TEL/AML1+ acute lymphoblastic leukemia (ALL) is considered to be a distinct nosological entity with excellent prognosis, but recent studies have indicated significant clinical heterogeneity. OBJECTIVE: In this study, we attempted to estimate the incidence and clinical features of TEL/AML1+ ALL for the first time in a representative cohort of Greek pediatric patients. METHODS: One hundred twenty children (<16 years old) diagnosed with ALL (107 of B-cell origin, 13 of T-cell origin) were screened for TEL/AML1 with interphase fluorescence in situ hybridization by using a commercial probe set. All patients were treated as either standard risk (SR) or high-risk (HR) cases according to a modified BFM-95 (Berlin-Frenkfurt-Munster) protocol. Follow-up ranged between 5 and 87 months (median: 45 months). RESULTS: Twenty-six patient (all of them will ALL of B-cell origin [24.3%]) were found to be positive for TEL/AML1. The presence of TEL/AML1 was significantly associated with younger age and lower white blood cell count at diagnosis but not with remission duration or overall survival rate. The number of children who relapsed (1 vs 7) or succumbed (1 vs 5) was comparable between the TEL/AML1+ and TEL/AML1− groups of children with ALL of B-cell origin. CONCLUSIONS: The incidence of TEL/AML1 in Greece seems comparable to that in other European and Mediterranean countries. As in most European studies, the independent prognostic value of TEL/AML1 is in doubt, because it is closely associated with other favorable factors. In this series, the modification of the therapeutic regimen (ie, omission of the SR arm) may be responsible for the similar outcome in TEL/AML1+ and TEL/AML1− cases, because it seems to lower the relapse risk for all children with ALL.

Clonal evolution is a prognostic factor for the clinical progression of monoclonal B-cell lymphocytosis

Monoclonal B-cell lymphocytosis (MBL) has attracted intensive research as the prelude of chronic lymphoproliferative disorders, mainly chronic lymphocytic leukemia (CLL).1 According to current criteria, MBL is a preclinical condition characterized by monoclonal B-cell expansions at small concentrations (<5 × 109 cells/l) in the peripheral blood of otherwise healthy individuals.2, 3 It is now obvious that MBL is a highly heterogeneous entity regarding the immunophenotypic characteristics and the B-cell clone burden.4, 5, 6 In immunophenotypic terms, MBL is distinguished into three main categories: (i) CLL-like (CD5+CD20dimCD23+sIglow) accounting for 70–75% of all cases; (ii) atypical (CD5+CD20bright/+), mainly CD23dim/−; and (iii) CD5neg MBL.2, 3 Based on the number of monoclonal B-cells, MBL is divided into low and high-count, each with a clearly different clinical course.5, 6, 7 Low-count MBL is a non-progressive entity with a normal absolute B-cell count, whereas high-count or ‘clinical’ MBL (cMBL) is characterized by absolute lymphocytosis and progresses to CLL at a rate of ~1–2% per year.8, 9