Acquired chromosome 11q deletion involving the ataxia teleangiectasia locus in B-cell non-Hodgkin's lymphoma: correlation with clinicobiologic features.

PURPOSE: To study the clinicobiologic significance of acquired 11q deletions involving the ataxia teleangiectasia locus (ATM+/-) in B-cell non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: Fifty-three indolent lymphomas and 82 aggressive lymphomas were studied by conventional cytogenetic analysis and by fluorescence in situ hybridization using an 11q22-23 probe recognizing ATM sequences. Pertinent clinical data were collected. RESULTS: A hemizygous ATM deletion was seen in 44% to 88% of the interphase cells in 15 cases (11.1%); four patients had an indolent lymphoma (follicular center cell lymphoma), and 11 patients had an aggressive lymphoma (five mantle-cell lymphomas [MCLs] and six diffuse large-cell lymphomas). Dual-color hybridization studies showed ATM deletion to be possibly a secondary aberration in three patients with MCL. Ten out of 15 ATM+/- patients had a complex karyotype, 11 out of 15 had more than 90% abnormal metaphases (AA karyotype status), and +12, 13q14 deletion, and 17p13 deletion were seen in seven, four, and five cases, respectively. Patients with ATM+/- more frequently had a complex karyotype (P =.01) and the AA karyotype (P =.04) compared with patients without ATM+/-. With the exception of a poor performance status (P =.001), no correlation was found between ATM+/-, initial clinical variables, and complete remission rate; whereas a highly significant association was found with shorter survival (P <.0001). This cytogenetic lesion maintained its prognostic importance in multivariate analysis (P =.0004), along with performance status (P =.0006), serum lactate dehydrogenase level (P =.03), splenomegaly (P =.01), and histologic grade (P =.03). When analyzing indolent lymphomas and aggressive lymphomas separately, ATM+/- maintained its prognostic importance as an independent variable in both histologic groups (P =.0001 and P =.016, respectively). CONCLUSION: Though possibly not representing a primary genetic lesion in the majority of cases, the acquired ATM+/- status has clinicobiologic importance in NHL, possibly representing a major cytogenetic determinant of outcome.

Maxillo-ethmoidal chloroma in acute myeloid leukaemia: case report.

Chloroma, also called Granulocytic Sarcoma or Myeloid Sarcoma, is a rare malignant extra-medullary neoplasm of myeloid precursor cells. It is usually associated with myelo-proliferative disorders but its appearance may precede the onset of leukaemia. Chloroma may be found in several extracranial sites. Involvement of the head and neck region is uncommon. Differential diagnosis is often difficult and includes acute lymphoblastic leukaemia, large cell NHL, lymphoblastic lymphoma and Ewing's sarcoma. The case is presented of a maxillo-ethmoidal chloroma occurring in a case of poor prognosis acute myeloid leukaemia, emphasizing the clinical and cyto-histological features and problems concerning differential diagnosis.

Cytogenetic and molecular cytogenetic characterization of 6 new cases of idiopathic hypereosinophilic syndrome.

BACKGROUND AND OBJECTIVE: Idiopathic hypereosinophilic syndrome (HES) is defined as a peripheral blood eosiniphilia greater than 1, 500 cells/microL for longer than 6 months, absence of other apparent etiologies for eosinophilia and signs and symptoms of organ involvement. HES may be a reactive condition or a chronic myeloproliferative disorder but scanty information is available concerning its cytogenetic profile. DESIGN AND METHODS: Six patients with HES were studied by cytogenetic analysis. To increase the sensitivity of cytogenetic analysis, interphase FISH studies were performed to detect some cryptic chromosomal lesions involving the regions known to be frequently involved in myeloproliferative disorders (i.e. BCR/ABL, 5q31, 7q31.1, 11q23, 13q14, 17p13). Clinical parameters were recorded in all patients. RESULTS: A 3q deletion was detected in one patient; two unrelated clones with +14 and +11 were present in another patient who had a cryptic 5q31 deletion as disclosed by FISH; both patients had a mild clinical course. The 5q31 deletion was shown to involve the eosinophilic lineage and not the lymphoid cells. No chromosome abnormalities were found by karyotyping or interphase FISH in the remaining 4 cases. In two of these cases the clinical course was aggressive, with progressive leukocytosis and marked splenomegaly in one patient, central nervous system and cardiac involvement as well as bone marrow failure in the other. INTERPRETATION AND CONCLUSIONS: The 3q deletion, +11 and +14, and a cryptic 5q31 deletion involving the cells of the eosinophilic lineage are three novel chromosome abnormalities occurring in HES. We did not find a correlation between evolving or aggressive disease and the presence of chromosome anomalies. Our data confirm that HES is a clinically and biologically heterogeneous condition and suggest that more cases need to be studied to identify clinically significant chromosome changes in this rare condition. Some patients may benefit from treatment with interferon.

Molecular cytogenetic characterization of marginal zone B-cell lymphoma: correlation with clinicopathologic findings in 14 cases.

BACKGROUND AND OBJECTIVES: To improve the definition of the incidence and significance of chromosome lesions occurring in marginal zone B-cell lymphoma (MZBCL). DESIGN AND METHODS: Fourteen cases of MZBCL diagnosed according to the REAL classification were studied by conventional chromosome analysis (CCA) and by interphase fluorescence in situ hybridization (FISH) using the following probes: 3q27/BCL6, 6q21, 7q31, 9p21/p16, 11q22/ATM, 13q14, 17p13, centromeres of #3, #7, #12. Pertinent clinical data were collected. RESULTS: Primary disease presentation consisted of histologically documented splenic MZBCL in 9 cases, nodal MZBCL in 3 cases and extra-nodal MZBCL in 2 cases. Four cases showed evolution into a high-grade lymphoma, due to the presence of a predominant large cell or blast cell component. Clonal karyotype anomalies were detected by CCA in 12 cases, 6 of which had a complex karyotype, including all 4 cases with high-grade histology. Interphase FISH confirmed cytogenetic data and revealed several cryptic chromosomal lesions. Overall, total/partial +12 was found in five cases; 13q14 and 17p13 deletion were found in four cases each; +3, 7q31 deletion and a BCL6 split signal were found in three cases; deletions at 6q21 and 11q22.3 in two cases each; +7 and a 9p21 deletion were found in one case each. INTERPRETATION AND CONCLUSIONS: i) Besides +3 and 7q-, 13q14 deletion, total/partial +12, BCL6 rearrangement, and deletions at 6q21, 11q22-23, and 17p13.3 are relatively frequent events in MZBCL; ii) unlike in mantle cell lymphoma, 9p21 deletion occurred infrequently in MZBCL; iii) a switch into high grade histology is usually associated with complex chromosome defects, including 6q-, 11q-, +12, and 17p.

Four novel non-random chromosome rearrangements in B-cell chronic lymphocytic leukaemia: 6p24-25 and 12p12-13 translocations, 4q21 anomalies and monosomy 21.

Nine patients with previously unreported chromosome changes were identified among 209 B-cell chronic lymphocytic leukaemia (CLL) cases: three patients had a translocation involving 6p24-25; three had a 12p12-13 translocation; two had 4q21 involvement (one with coexisting 6p anomaly); and two had monosomy 21. Interphase fluorescence in situ hybridization (FISH) detected some cryptic aberrations (+12, 6q-, 17p-, 11q-) in those patients with 6p translocations, whereas only a cytogenetically undetected 13q14 deletion was found in the remaining cases. Atypical morphology was noted in six cases, including both cases with monosomy 21, two cases with 6p and 4q21 anomaly and one case with 12p involvement. Four of these cases also had more than one phenotype deviation with respect to the classical CLL phenotype. Disease progression after 21-51 months (median 41) was noted in two cases with 6p and 4q21 involvement and in one case with 12p anomaly and monosomy 21. We arrived at the following conclusions: (i) 6p24-25 and, possibly, 4q21 lesions represent non-random events in CLL, occurring in association with other well-known unbalanced rearrangements; (ii) 12p rearrangements and monosomy 21 may possibly represent early chromosome defects that are not associated with the classical DNA gains and losses known to be present in the majority of CLL; and (iii) atypical morphology and immunophenotype as well as disease progression were frequently observed in these cases

13q14 deletion in non-Hodgkin's lymphoma: correlation with clinicopathologic features.

BACKGROUND AND OBJECTIVE: 13q14 deletion frequently occurs as a single anomaly in chronic lymphocytic leukemia (CLL) with favorable prognosis. This study was performed to assess the distribution of 13q14 deletion in non-Hodgkin's lymphoma (NHL) and to analyze its correlation with salient clinicopathologic features. DESIGN AND METHODS: One hundred and twenty-five NHL were analyzed by cytogenetics and by interphase fluorescence in situ hybridization (FISH), using a 13q14 cosmid probe recognizing DNA sequences between the Rb gene and the D13S25 marker. Clinical records all patients were surveyed. RESULTS: A 13q14 rearrangement was present in the stemline in 10 patients; 15 additional cases were shown by FISH to carry 13q14 deletion in 55-90% of the interphase cells, giving a 20% overall incidence for this anomaly. Six of 44 patients had a low-grade NHL, 14/28 had mantle cell lymphoma (MCL), 5/42 had a high grade NHL (p<0.0001). There was not correlation between 13q, karyotype status and complexity. A statistically significant association was found between 13q-, presence of splenomegaly and PB involvement, lower probability of attaining complete remission (CR) and shorter survival. These findings were not simply a function of the association of 13q- with MCL. In multivariate analysis, a complex karyotype had prognostic importance (p=0.0078), along with age (p=0.01), histology (p=0.001), LDH (p=0.03), PS (p=0.001), sex (p=0.03) and splenomegaly (p=0.02). INTERPRETATION AND CONCLUSIONS: 13q14 deletion represented an early chromosome change and showed a preferential association with MCL, though it was found in virtually all principal histologic subtypes, irrespective of clinical stage, karyotype status and complexity. Patients with 13q14 deletions had a low CR rate, suggesting that genes relevant to lymphomagenesis are located in this chromosome segment that warrants molecular cytogenetic investigation.

Exposure to myelotoxic agents and myelodysplasia: case-control study and correlation with clinicobiological findings.

To better define the role of exposure to myelotoxic agents in the genesis of myelodysplastic syndrome (MDS), we carried out (a) a case-control study for the determination of the relative risk (RR) of developing MDS, including 178 consecutive patients and 178 sex- and age-matched controls: (b) a study of clinicobiological features in MDS arising after occupational exposure to myelotoxic agents and in MDS in 'non-exposed' patients. The definition of the 'exposure' status was based on a predetermined questionnaire, with calculation of an 'exposure' index (hours/day x days/year x years). Cumulative exposure to pesticides or to organic solvents, for >2400 h, was recorded in 48 and 25 MDS patients, respectively, compared to 27 and four controls (P<0.00001; RR 3.74; 95% confidence interval 2.02-5.37). Older age and an excess of refractory anaemia with ringed sideroblasts and refractory anaemia with excess of blasts was noted among 'exposed' MDS-patients (group 1), compared to non-exposed MDS-patients (group 2). 68.3% patients in group 1 had clonal chromosome changes, compared with 43.2% patients in group 2. Complex karyotypes, -7/7q-, -5/5q-, +8, 7p and 17p aberrations were seen more frequently in group 1, whereas a normal karyotype, isolated 5q- or 20q- occurred more frequently in group 2. The association of exposure to myelotoxic agents with older age at presentation and with unfavourable chromosome changes accounted for the shorter survival observed in 'exposed' patients. These data show that occupational exposure to pesticides and organic solvents in our region resulted in an increased RR of developing MDS and that a distinct cytogenetic profile was associated with MDS in 'exposed' patients. These findings provide strong indirect evidence that these agents may play a role in the pathogenesis of MDS, preferentially targeting some of the chromosome regions which are frequently involved in therapy-related myeloid neoplasias.