Chromosome 11q rearrangements in B non Hodgkin''s lymphoma

The clinical features, morphology and immunophenotype of 20 cases of B non Hodgkin's lymphoma (B-NHL) with chromosome abnormalities involving 11q13-14 were studied, to determine if this abnormality was closely associated with a specific sub-type of B-NHL. A t(11;14)(q13;q32) was found in 11 cases of intermediately differentiated lymphocytic lymphoma (IDLL). A breakpoint in the major translocation cluster of the BCL-1 locus was found in six of these cases. These patients were male with lymphomatous involvement of the bone marrow, marked splenomegaly and frequently had mucosa associated lymphoid tissue involvement. One patient with IDLL had a t(8;11)(p21;q13) and a rearranged BCL-1 locus, suggesting that this may be a variant of t(11;14)(q13;q32). Diagnoses of IDLL, chronic lymphocytic leukaemia, lymphoplasmacytic lymphoma and monocytoid B cell lymphoma were made in all but one of the remaining cases. These cases had either a translocation involving 11q13-14 and various partner chromosomes or an 11q13 deletion. This study demonstrates that 11q abnormalities occur mainly in a group of low-grade B-NHL of non follicle centre cell lineage.     

t(14;18)(q32;q21)-bearing pleural MALT lymphoma with IgM paraproteinemia: value of detection of specific cytogenetic abnormalities in the differential diagnosis of MALT lymphoma and lymphoplasmacytic lymphoma

A 67-year-old woman presented with a pleural effusion and a tumor in the right pleural wall. Histological examination of thoracoscopic tumor and pleural biopsy specimens showed infiltration by medium sized cells, some of which showed plasmacytoid differentiation. In view of the presence of IgM paraproteinemia and bone marrow involvement by lymphoma cells, the patient was diagnosed tentatively as having lymphoplasmacytic lymphoma (LPL). However, chromosomal analysis of the cells in the pleural fluid detected t(14;18)(q32;q21), while fluorescence in situ hybridization was positive for 11% of the MALT1 split signal. Because of the presence of characteristic genetic abnormalities and notable extranodal involvement, the patient was diagnosed as having MALT lymphoma. She was treated with three courses of cladribine and rituximab, and achieved complete regression of the tumor. In this case the detection of t(14;18)(q32;q21) involving IGH and MALT1 was useful for the differential diagnosis of LPL and MALT lymphoma.     

Fluorescence In Situ Hybridization Detection of Chromosome IGH/BCL2 Translocations from Paraffin-Embedded Tissue: Evaluation in Follicular Lymphoma

Follicular lymphoma is categorized as low-grade lymphoma because of the long median survival, but the disease is difficult to cure because of frequent recurrence. The t(14;18)(q32;q21) associated with follicular lymphoma juxtaposes a portion of BCL-2 (18q21) and IGH(14q32); the result is bcl-2 overexpression. In this study, a highly sensitive 2-color fluorescence in situ hybridization (FISH) method was used to detect t(14;18)(q32;q21) in the nuclei of paraffin-embedded tissue sections. Fourteen specimens, including 11 samples from follicular lymphoma and 3 samples from diffuse large cell lymphoma, for which results of karyotype study and paraffin-embedded tissues were available were selected for FISH study. The FISH results were compared with results of karyotype study of the lymph nodes involved in lymphoma. Among our 11 patients with the diagnosis of follicular lymphoma in whom karyotype study was performed, 8 had t(14;18)(q32;q21) in karyotype analysis, and 7 of these patients had a positive pattern in FISH analysis. In 1 case, FISH analysis was difficult because of weak signals. All 3 patients with diffuse large cell lymphoma and t(14;18)(q32;q21) in karyotype analysis had a positive pattern in FISH analysis. In 3 cases of follicular lymphoma without t(14;18)(q32;q21) in karyotype analysis, FISH did not show a positive pattern. Therefore the FISH assay in tissue was found to be very sensitive in detection of IGH/BCL2 translocation and was helpful in diagnosis of follicular lymphoma or in clarification of the cell origin of lymphoma when karyotype analysis was not available. Performing FISH on paraffin sections also is useful because we can identify cells with genetic abnormalities in the tumor and make a retrospective cytogenetic diagnosis even with old paraffin-embedded specimens. Int J Hematol. 2003;78:154-159.     

Significance of extra 18q- chromosome in Japanese t(14;18)-positive lymphoma

Karyotype evolution of t(14;18)-positive lymphoma was studied in 13 Japanese patients. The extra 18q- chromosome, found in six of ten patients with complex karyotypes, was the most common change subsequent to a t(14;18)(q32;q21) chromosome translocation. The additional change was interpreted as being a duplication of an 18q- derived from a t(14;18). The six patients had transformed histology of follicular small cleaved cell lymphoma or diffuse large cell lymphoma, and five of them had extranodal expansion associated with a poor prognosis. These findings indicate that the extra 18q-, together with other chromosome abnormalities, is closely associated with the advanced grade disease of t(14;18)-positive lymphoma, and the extra chromosome is evolutionally comparable with the second Philadelphia (Ph1) chromosome often found in the blastic phase of chronic myelocytic leukemia carrying a t(9;22)(q34;q11). In addition, since the extra 18q- is rarely found in American patients with t(14;18)-positive lymphoma, there appears to be a difference in the karyotype evolution between Japanese and American patients.     

Diffuse large B-cell lymphoma carrying both t(3 ; 7)(q27 ; p12) and t(8 ; 14)(q24 ; q32)

We report a 60-year-old man with diffuse large B-cell lymphoma harboring both t(3 ; 7)(q27 ; p12) and t(8 ; 14)(q24 ; q32). Although he received six courses of conventional combination chemotherapy plus rituximab, early relapse occurred. Four courses of an intensive salvage regimen and high-dose chemotherapy with autologous peripheral blood stem cell transplantation were performed. The patient has remained in complete remission for over 24 months. This case is noteworthy because both genetic abnormalities are implicated in lymphomagenesis.     

Cytogenetic studies in splenic lymphoma with villous lymphocytes

Summary. We report the cytogenetic findings on 31 cases of splenic lymphoma with villous lymphocytes (SLVL). TPA stimulated cells from peripheral blood (28 cases), spleen (two cases) and lymph node (one case) with SLVL have been analysed. A clonal chromosome abnormality was found in 27/31 patients (87%): this was identified as a simple abnormality in 12 cases and a complex one in 15. Four recurring abnormalities were seen: t(11:14) (q13:q32)in five patients, deletions or translocations involving 7q in seven patients. iso 17q in four patients and translocations involving 2p11 in four patients. The high frequency of clonal chromosome abnormalities in SLVL contrasts with the usually benign clinical course of this disease.
Abnormalities found frequently in patients with chronic lymphocytic leukaemia (CLL) such as trisosmy 12 and deletions or translocations involving 13q14 were each seen in only one patient. No case had the t(14:18) characteristic of follicular lymphoma.
Our findings demonstrate the high frequency of clonal and often complex chromosome abnormalities in SLVL. Although a unique chromosome rearrangement has not been identified, a pattern of four recurrent abnormalities has emerged. Our results suggest that SLVL is distinct on cytogenetic grounds from B-CLL and follicular lymphoma but shows similarity with mantle cell lymphoma, lymphoplasmacytic lymphoma and B-PLL.     

LightCycler-based quantitative real-time PCR monitoring of patients with follicular lymphoma receiving rituximab in combination with conventional or high-dose cytotoxic chemotherapy

OBJECTIVES: Quantitative real-time polymerase chain reaction (qPCR) is a suitable method to measure residual disease in hematological malignancies. Our objective was to assess a LightCycler-based qPCR for t(14;18)(q32;q21)(IgH/bcl-2)-positive cells quantification in the context of clinical and morphopathological characteristics of patients with follicular lymphoma treated with rituximab (R) in combination with conventional or high-dose chemotherapy. METHODS: A total of 270 bone marrow (BM) and peripheral blood (PB) samples collected from 52 patients with follicular lymphoma at diagnosis or at relapse before or sequentially during therapy were examined by qPCR and nested-PCR. RESULTS: A greater amount of t(14;18)-positive cells was observed in BM in comparison with PB in 76% of paired samples. The presence and number of t(14;18)-positive cells in BM and PB correlated with lymphoma activity. Significantly higher numbers of lymphoma cells were found in patients under non-remission compared with patients in clinical remission. During non-remission, 10-fold higher numbers were measured at relapse than at diagnosis. During remission, significantly higher levels were found in partial compared with complete remission. During first-line therapy, R/cyclophosphamide/adriamycin/vincristine/prednisone (CHOP) had higher in vivo purging ability than R/fludarabine/mitoxantrone (FM). After R/high-dose cytosine-arabinoside and mitoxantrone (HAM) or R/carmustine/etoposide/cytarabine/melphalan (BEAM), the level of t(14;18)-positive cells dropped below the detection limit in 80% of patients. CONCLUSIONS: LightCycler qPCR is a reliable method for quantitative molecular monitoring of t(14;18)-positive cells in BM and PB of patients with follicular lymphoma. It reflects the clinical characteristics of patients and allows assessment of response to different treatment regimens on a molecular level.     

Diagnostic challenges in a case of B cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

Unclassifiable B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) is a recently recognized category of mature B-cell lymphoma. This represents a heterogeneous group of diseases which often pose diagnostic problems in clinical practice, yet its distinction from DLBCL to BL is important for its therapeutic and prognostic implications. We report the challenging diagnostic process of a 60-year-old man. He had a CD10 and BCL2-positive, BCL6-negative B-cell malignancy with loss of multiple B-cell markers including surface immunoglobulin. The karyotype was complex and unusual, including t(2;18)(p12;q21), t(8;14)(q24;q32) and a derivative chromosome 22 mimicking a Philadelphia chromosome that led to initial diagnostic confusion. A triple-hit gray zone B-cell lymphoma with rearrangements of MYC, BCL2, BCL6, both alleles of IGH and likely IGK and IGL was finally diagnosed upon additional fluorescence in situ hybridization (FISH) studies. His disease was nonresponsive to intensive combination chemotherapy and he died 4 months after presentation. This case illustrates the diagnostic difficulty encountered in such group of B-cell lymphomas and emphasizes the need to integrate morphological, immunophenotypic and genetic data in making a diagnosis.     

Pulmonary MALT lymphoma with macroglobulinemia

An 84-year-old man was diagnosed as having pulmonary MALT lymphoma in January 1997. Six years later, he was admitted to our hospital with coughing and dyspnea in November 2003. Dissemination of MALT lymphoma was confirmed by findings of pleural effusion and bone marrow aspiration. A FISH analysis of cells from the pleural effusion revealed t(11;18)(q21;q21) and the serum level of IgM was 8,600 mg/dl (M-protein). The diagnosis of secondary macroglobulinemia was made. The patient received rituximab monotherapy because he was very elderly. Pleural effusion has not been seen after the administration of rituximab, although there have been no changes in the lung mass and serum values of M-protein.     

Follicular lymphoma in two brothers]

Two brothers, whose parents had a history of exposure to atomic bomb radiation, developed non-Hodgkin's lymphoma. The younger brother, a 48-year-old man, was diagnosed as having follicular small-cleaved cell lymphoma in October, 1996. He had extranodal lymphoma involvement of the right kidney, bone marrow and skin, in addition to generalized lymphadenopathy. He was treated with intermittent COP chemotherapy, and good control of the lymphoma was obtained. The elder brother, aged 50 years, was diagnosed as having follicular mixed cell lymphoma in May, 1998. He also had extranodal lymphoma involvement of the right parotid gland and bone marrow, as well as generalized lymphadenopathy. After one course of CHOP chemotherapy, he developed paresis of the lower legs and was found to have a mass at the Th5-6 vertebrae by CT scan. After four courses of CHOP chemotherapy followed by ESHAP chemotherapy and radiotherapy, he achieved complete remission, and has since been well. Follicular lymphoma occurring among siblings is rare. Further cytogenetic and molecular studies may provide a better understanding of its etiology.     

Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive

Chromosomal translocations involving t(14;18)(q32;q21) and the chromosome 3q27 region are common in B-cell non-Hodgkin lymphoma of germinal center cell origin. Grade 3B follicular lymphoma (FL), consisting almost exclusively of centroblasts, is a distinct subgroup of follicular lymphomas that has more in common clinically with the aggressive diffuse large B-cell lymphomas than with their indolent FL grade 1 and 2 counterparts. We studied the cytogenetic and molecular genetic aberrations by classic cytogenetics, polymerase chain reaction, Southern blot hybridization, and fluorescence in situ hybridization, with special emphasis on t(14;18), affecting bcl-2, and 3q27 rearrangement, affecting bcl-6, in 32 cases of FL grade 3B. Three distinctive subgroups were identified based upon the existence of breakpoint 3q27, a translocation t(14;18), or the absence of both. Group I involved a t(14;18) and no 3q27 aberrations (n = 13); group II was without a t(14;18) and without 3q27 aberrations (n = 9), but had other cytogenetic aberrations; and group III was without a t(14;18) but with aberrations involving 3q27 (n = 10). None of the FL grade 3B cases harbored both a t(14;18) and 3q27 aberration. These results, in particular the finding of a mutual exclusiveness of bcl-2 and bcl-6 rearrangement, indicate at least 3 different pathways of oncogenesis in FL grade 3B. FL grade 3B with bcl-2 rearrangement probably is part of the same entity as the other follicular lymphomas (1, 2, 3A), whereas the cases with 3q27 abnormalities or other unrelated translocations are more closely related to the majority of diffuse large-cell lymphomas of germinal center cell origin.     

Ovarian follicular lymphoma: a case report and review of the literature

Primary ovarian lymphoma is extremely rare, and such a case is reported here. The patient was a 54-year-old Japanese female with abnormal genital bleeding. Pelvic CT and MRI showed a right ovarian tumor with a diameter of 7 cm and an irregular border. With the diagnosis of a right ovarian tumor, the patient underwent a simple hysterectomy and bilateral salpingo-oophorectomy. Microscopic examination of the right ovarian tumor revealed vaguely nodular growth of small lymphoid cells. They were CD10+, Bcl-2+, Cyclin D1- and CD21-, although CD21+ follicular dendritic cell clusters were present as a background component in each vague nodule. A conventional cytogenetic analysis revealed t(14;18)(q32;q21), and somatic hypermutation of the variable region of the immunoglobulin heavy chain gene (IgH) was confirmed by direct sequencing of subcloned DNA samples derived from PCR amplicons. These findings led us to characterize the lesion as follicular lymphoma, grade 1. The patient was free of detectable disease 9 months after initiation of post-surgical chemotherapy. Since the prognosis for primary ovarian lymphoma is relatively favorable in many cases, it is important to establish therapeutic methods for the cure of this disease using chemotherapy and radiotherapy without radical surgery.     

t(9;13)(q34;q12) chromosomal translocation persisting 4 years post autologous bone marrow transplantation for secondary AML despite morphological remission

A 42-year-old male patient with a history of occupational exposure to benzene presented with pancytopenia. His bone marrow showed evidence of trilineage dysplasia and cytogenetic analysis revealed a unique t(9;13)(q34:q12) translocation. Five months after diagnosis he developed secondary AML. He was treated with four courses of chemotherapy and an autologous bone marrow transplantation (BMT). Four years post-transplantation he remains in haematological and morphological remission though the cytogenetic abnormality is still present in all metaphases examined.     

t(3;22)(q27;q11): a novel translocation associated with diffuse non- Hodgkin's lymphoma [see comments]

Of 187 specimens of non-Hodgkin's lymphoma and four hyperplastic lymphoid proliferations with clonal chromosome abnormalities ascertained serially over a 4 1/2-year period, nine cases with t(3;22)(q27;q11) were identified. Seven of the lymphomas were diffuse tumors, predominantly large cell type. The eighth tumor, a follicular small cleaved cell lymphoma, exhibited a t(3;22) and a t(14;18)(q32;q21). The ninth case was a lymph node from a human immunodeficiency virus-positive patient which showed atypical hyperplasia. Overall survival of t(3;22) diffuse lymphoma patients was not different from that of patients with abnormal karyotypes without t(3;22). The t(3;22) diffuse tumors studied showed a disproportionate frequency of lambda light chain on their cell surfaces, a finding similar to that observed in t(8;22)(q24;q11) Burkitt's lymphomas. Our results indicate that the t(3;22)(q27;q11) is the third most common recurring translocation in diffuse non-Hodgkin's lymphoma.     

Aggressive natural killer cell leukemia/lymphoma: a comprehensive cytogenetic study by spectral karyotyping

 A 38-year-old male presented with fever and hepatosplenomegaly. Cells that had infiltrated to the bone marrow were consistent immunophenotypically and genotypically with natural killer (NK) cells. Oligoclonal Epstein-Barr virus infection was detected in the bone marrow cells. The patient was diagnosed as a case of aggressive NK cell leukemia/lymphoma. Combined chemotherapy was not effective and death occurred shortly after presentation. Although the karyotype of this case was too complicated to be accurately identified only by G-banding, spectral karyotyping (SKY) analysis not only identified all chromosomal materials of unknown origin, but also detected the cryptic translocation on the apparently normal chromosome. Moreover, SKY analysis identified der(4)t(4;14)(q12;q11.2). The chromosomal band 14q11.2 is a recurring breakpoint in T-cell non-Hodgkin's lymphoma, and is also the locus of the δ chain of the T-cell receptor. To our knowledge, t(4;14)(q12;q11.2) in T-cell or NK-cell malignancies has not been previously reported. Received: 6 September 1999 / Accepted: 31 January 2000     

Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T cell leukemia- lymphoma. Fifth International Workshop on Chromosomes in Leukemia- Lymphoma

To correlate cytogenetic findings with histology and immunophenotype, 260 newly diagnosed patients with non-Hodgkin's lymphoma (NHL) and 31 with adult T cell leukemia/lymphoma (ATL) were studied at the Fifth International Workshop on Chromosomes in Leukemia-Lymphoma. Clonal chromosome abnormalities were found in 85% of cases of NHL and in all cases of ATL. The most significant associations of histology with cytogenetics involved the 8q24 and 14;18 translocations. Of 23 NHL patients with an 8q24 translocation, 20 (87%) had small noncleaved cell (SNC) lymphoma. Of 57 NHL patients with a t(14;18)(q32;q21), 37 (65%) had a follicular lymphoma, and at least 13 others (23%) had a diffuse lymphoma of follicular center cell origin. Five others including two who also had an 8q24 translocation had SNC lymphoma; tumors in these patients lacked the monomorphic features seen in those with only an 8q24 translocation. The most striking associations of immunology with cytogenetics involved rearrangements of 14q11-13, abnormalities of 1p, trisomy 3, and trisomy 12. Abnormalities of 14q11-13 were correlated with T cell disease. Among 138 NHL and 24 ATL cases that lacked involvement of 8q24, t(14;18), or rearrangements of 14q11-13, abnormalities of 1p and trisomy 3 were significantly associated with the T cell phenotype (P less than .01) and trisomy 12 with the B cell phenotype (P less than .01). No karyotype difference was found between Japanese ATL and non-Japanese T cell lymphomas except that +3 occurred more often in the former (P = .06). Although the 8q24 translocations in 23 patients were distributed relatively equally among geographic regions (United States, ten; Europe, ten; Japan, three), the t(14;18) in 57 patients was much less frequently seen in Japan than in the other parts of the world (United States, 31; Europe, 21; Australia, four; Japan, one). Thirty-nine chromosome bands had breaks in five or more cases; a number of protooncogenes and genes related to lymphocyte function located in these bands are likely to be involved in the development of lymphoma. Thus, besides confirming the close association of particular chromosome abnormalities with histology, we have identified a number of new associations that merit molecular analysis.     

Quantitative assessment of disease involvement by follicular lymphoma using real-time polymerase chain reaction measurement of t(14;18)-carrying cells

Chromosomal translocation t(14:18)(q32;q21) is one of the most common karyotypic abnormalities in non-Hodgkin's lymphomas. It occurs in more than 85% of follicular lymphoma (FL) cases. Real-time polymerase chain reaction (Q-Rt-PCR) analysis using double-labeled fluorogenic probes is a new tool in the detection and quantification of t(14;18)-carrying cells. We analyzed 239 specimens with Q-Rt-PCR to detect and quantify t(14;18)-carrying cells. To investigate the clinical usefulness of the quantitative assessment, we analyzed the clinical correlation with 92 FL patients of varying clinical status. Of 59 previously untreated patients, patients with stage IV disease had significantly higher quantities of t(14;18)-carrying cells measurable in the bone marrow or the peripheral blood than patients in clinical stages I to III (P = .003 and .043, respectively). Moreover, of the 33 posttherapy patients. the patients in complete remission appeared to have lower detectable levels of t(14;18)-carrying cells than patients in partial remission or with recurrent disease. Q-Rt-PCR permits a sensitive and quantitative assessment of the extent of disease involvement in patients with t(14;18)-carrying FL. The technique has the potential to be a useful tool in the diagnosis of FL, disease assessment, and prognosticating patients' clinical outcomes.     

Chromosomal abnormalities in untreated patients with non-Hodgkin's lymphoma: associations with histology, clinical characteristics, and treatment outcome. The Nebraska Lymphoma Study Group

We describe the chromosomal abnormalities found in 104 previously untreated patients with non-Hodgkin's lymphoma (NHL) and the correlations of these abnormalities with disease characteristics. The cytogenetic method used was a 24- to 48-hour culture, followed by G- banding. Several significant associations were discovered. A trisomy 3 was correlated with high-grade NHL. In the patients with an immunoblastic NHL, an abnormal chromosome no. 3 or 6 was found significantly more frequently. As previously described, a t(14;18) was significantly correlated with a follicular growth pattern. Abnormalities on chromosome no. 17 were correlated with a diffuse histology and a shorter survival. A shorter survival was also correlated with a +5, +6, +18, all abnormalities on chromosome no. 5, or involvement of breakpoint 14q11-12. In a multivariate analysis, these chromosomal abnormalities appeared to be independent prognostic factors and correlated with survival more strongly than any traditional prognostic variable. Patients with a t(11;14)(q13;q32) had an elevated lactate dehydrogenase (LDH). Skin infiltration was correlated with abnormalities on 2p. Abnormalities involving breakpoints 6q11-16 were correlated with B symptoms. Patients with abnormalities involving breakpoints 3q21-25 and 13q21-24 had more frequent bulky disease. The correlations of certain clinical findings with specific chromosomal abnormalities might help unveil the pathogenetic mechanisms of NHL and tailor treatment regimens.