Hans Vandenberghe

Trisomy 3 in marginal zone B-cell lymphoma: A study based on cytogenetic analysis and fluorescence in situ hybridization

Trisomy 3 represents the most frequent and consistent chromosomal abnormality characterizing the recently defined entity marginal zone B‐cell lymphoma (MZBCL). By cytogenetic analysis and/or fluorescence in situ hybridization (FISH) on interphase nuclei we found an increased copy number of chromosome 3 in 22/36 (61%) successfully analysed cases, including 8/12 cases with extranodal MZBCL, 8/13 cases with nodal MZBCL, and 6/11 patients with splenic MZBCL. Sensitivity of interphase cytogenetics was somewhat higher than that of conventional cytogenetic investigation. Structural chromosomal changes involving at least one chromosome 3 were seen in 11/20 cases with an increased copy number of chromosome 3: +del(3)(p13) was demonstrated in three cases, and was the sole chromosomal abnormality in one of them; +i(3)(q10) was seen in two other patients; and rearrangements involving various breakpoints on the long arm of chromosome 3 were found in the remaining cases. FISH on metaphase spreads confirmed these structural abnormalities and additionally showed two unexpected translocations involving chromosome 3. We conclude that: (1) trisomy 3 occurs in a high proportion of extranodal, nodal and splenic MZBCL; (2) FISH on interphase nuclei is an additional and sensitive tool in detecting an increased copy number of chromosome 3 in MZBCL; (3) additional structural abnormalities involving the long arm of chromosome 3 are frequent but non‐recurrent and are perhaps secondary changes; and (4) abnormalities such as +del(3)(p13) and +i(3)(q10) suggest that genes located on the long arm of chromosome 3 are of particular importance in the pathogenesis of MZBCL.

Morphologic, immunologic and cytogenetic studies in erythroleukaemia : evidence for multilineage involvement and identification of two distinct cytogenetic-clinicopathological types

Summary. Clinical features, as well as morphology, immunophenotype and cytogenetics were retrospectively studied in 20 patients with an original diagnosis of erythroleukaemia (EL) reclassified according to the FAB criteria. Fifteen patients had de novo EL, five patients had therapy‐related EL. Myelodysplasia preceded the onset of EL in eight cases and myelodysplastic features involving multiple haemopoietic lineages were observed at leukaemia presentation in all cases. Immunologic findings confirmed multilineage involvement, showing sub‐populations of cells expressing platelet‐associated markers in more than 50% of cases tested and the presence of a myelomonocytic component, besides glycophorin A‐positive cells. Cytogenetically, major karyotype aberrations (MAKA), defined by the presence of three or more aberrant events in the same clone, were observed in 14 cases, minor karyotype aberrations (MIKA) were observed in four cases and normal karyotype in two cases. No differences in the cytological‐cytogenetic picture of our patients with de novo EL and with therapy‐related EL were found suggesting that aetiological factors and/or pathogenetic mechanisms common to EL and secondary leukaemia may exist. All patients with MAKA had leftward shift of erythropoiesis with proerythroblasts and basophilic erythroblasts usually representing more than 50% of all erythroid cells. In patients with MIKA or normal karyotype, maturation of erythroid cells, though morphologically abnormal, was quantitatively preserved and early erythroblasts never exceeded 25% of erythroid cells. Clinically, the haemoglobin level at presentation, as well as in the proportion of patients achieving complete remission after chemotherapy, appeared to be lower in the maturation arrest‐MAKA group as compared to the preserved maturation‐MIKA/normal karyotype group. Median survival was shorter in the former group (3.5 months) than in the latter (median 13 months). Morphologic‐immunologic‐cytogenetic studies thus allow for the identification of two distinct cytogenetic‐clinicopathological types of EL.

Multiple chromosomally distinct cell populations in myelodysplastic syndromes and their possible significance in the evolution of the disease

Summary. Serial chromosome investigations performed in untreated myelodysplastic syndromes (MDS) revealed that: (a) multiple chromosomaily unrelated cell populations may emerge during the course of the disease; (b) chromosome changes of the clonal type may disappear or become undetectable, and may or may not reappear during further evolution. The former of these phenomena was found in four cases and was consistently associated with clinical‐haematological progression of the disease to a more malignant form, including acute leukaemia. The second was apparently unrelated to clinical and haematological changes in the evolution pattern.

Myelodysplastic Syndromes With Bone-marrow Fibrosis - a Myelodysplastic Disorder With Proliferative Features

SummaryWe report on 22 patients with myelodysplastic syndrome (MDS), all of whom showed striking marrow fibrosis. Variable blood counts, often with teardrop poikilocytosis and a leukoerythroblastic picture, were present at diagnosis. Visceral enlargement was detected in 17 patients with a distinct splenomegaly in seven cases. All cases demonstrated dysplasia in at least two cell lineages. No specific cytogenetic abnormality seems to characterize this group of patients. Southern blot analysis showed no breakpoint cluster region rearrangement as observed in classical chronic myeloid leukemia. Ferrokinetic studies revealed quantitatively deficient erythropoiesis in all except two cases and an abnormally high fraction of ineffective erythropoiesis in all. Splenic erythropoiesis was present in eight patients. The median survival was 18 months. At the time of this report, 12 patients had died. The causes of death were disease progression (7 patients) and infection (5 patients). One might speculate that the present series of cases represents a transition between MDS and myeloproliferative disease, thereby dysplaying characteristics of both groups of diseases.

BCL6 gene rearrangements also occur in marginal zone B‐cell lymphoma

Marginal zone B‐cell lymphoma (MZBCL) represents a distinct subtype of B‐cell non‐Hodgkins lymphoma (NHL) which has been recently recognized and defined as a disease entity. Cytogenetically, these lymphomas reveal a high prevalence of trisomy 3, and recent data obtained by comparative genomic hybridization indicate that the chromosomal regions 3q21‐23 and 3q25‐29 might be of particular pathogenetic significance. We identified structural chromosomal abnormalities involving the region 3q27 and rearrangements of the BCL6 proto‐oncogene in three out of 34 (9%) well‐defined cases of extranodal, nodal and splenic MZBCL using cytogenetic analysis, Southern blot, and fluorescence in situ hybridization (FISH). All three cases were characterized by a t(3;14)(q27;q32). Two of them showed additional chromosomal abnormalities including trisomy 3, which was found in one case. The patients displayed extranodal disease and did not demonstrate any striking clinical and histological differences when compared with MZBCL lacking BCL6 rearrangement. The present study for the first time demonstrates the occurrence of t(3;14)/BCL6 gene rearrangement in MZBCL, thus suggesting a role of the BCL6 proto‐oncogene in the pathogenesis of MZBCL.

Rearrangements of the Short Arm of Chromosome No-6 in T-cell Lymphomas

Cytogenetic studies on four patients with T-cell lymphomas are reported. In all four the short arm of chromosome No. 6 (6p) was abnormal. In three cases it was involved in a translocation, and in one there was a deletion of the terminal part: del(6)(p23-24). One of the translocations could be identified as a t(2:6)(q24;p24). Identification was not possible in the others. These 6p anomalies were associated with complex structural and numerical abnormalities of other chromosomes in three out of four cases. In three patients chemo- and/or radiotherapy administration preceded cytogenetic investigations.

Trisomy 3 is a consistent chromosome change in malignant lymphoproliferative disorders preceded by cold agglutinin disease

Summary. Cold‐antibody autoimmune haemolytic anaemia is a rare entity that has been associated with a wide variety of pathological processes, including malignant lymphoproliferative disorders. In this retrospective study we recorded, as far as possible, clinical, haematological, immunological, morphological, pathological, cytogenetic and molecular data on 10 patients with cold agglutinin disease (CAD). Cytogenetic anomalies were found in four cases in which an underlying lymphoma could be evidenced. Trisomy 3 was the only recurrent aberration in our series. It was observed in all patients with abnormal karyotype, either as a complete trisomy or as a partial trisomy of the long arm. The importance of this particular karyotypic aberration in the monitoring of CAD is emphasized.

Minor myeloid component in Ph chromosome-positive acute lymphoblastic leukaemia: correlation with cytogenetic pattern and implication for poor response to therapy

Morphological, immunological and cytogenetic features were studied in 27 adults presenting with Ph chromosome‐positive acute lymphoblastic leukaemia (ALL), in correlation with clinical outcome.

Translocation t(8;10)(q12;p14) in lymphoproliferative disorders.

Cytogenetic studies were performed in two patients with a B-cell lymphoproliferative disease in progressive phase characterized by leukocytosis and important splenomegaly. In both patients an identical chromosome marker derived from a t(8;10)(q12;p14) translocation was found. This chromosome anomaly was associated with other abnormalities characteristic for lymphoid malignancies, i.e. a structural rearrangement of the long arm of chromosome 11 and a 14q+ in both patients. This new t(8;10) translocation may be a marker of accelerated phase in lymphoid disorders.