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The t(14;18)(q32;q21) is a cytogenetic hallmark of follicular lymphoma and also occurs in approximately 20% of diffuse large B-cell lymphomas of follicle center cell origin. Relatively few cases of chronic lymphocytic leukemia/small lymphocytic lymphoma with t(14;18) have been reported previously. We report the clinicopathologic, cytogenetic, and molecular genetic features of 12 patients with chronic lymphocytic leukemia associated with t(14;18). There were 9 men and 3 women, with a median age of 51 years at diagnosis. To date, 11 patients have required chemotherapy, 6 before coming to our institution. At last follow-up, 5 patients have died of disease. Karyotypic analysis showed that 10 cases had t(14;18) in the stemline and 2 cases in the sideline; t(14;18) was the sole abnormality in the stemline in 2 cases. In 11 cases, other abnormalities were identified in the stemline or sidelines, most commonly trisomy 12 in 6 cases. Trisomy 12 was associated with atypical morphology and immunophenotype. Of 8 cases tested, 7 showed somatically mutated immunoglobulin heavy chain variable region genes. We conclude that the t(14;18) in chronic lymphocytic leukemia is associated with relatively young age at diagnosis, mutated immunoglobulin heavy chain variable region genes, and a clinical course that usually requires chemotherapy. The cytogenetic findings, in particular, t(14;18) in the stemline in 10 cases and as the sole karyotypic abnormality in 2 cases, suggest that t(14;18) is an early pathogenetic event in this small subset of chronic lymphocytic leukemia cases., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The t(14;19)(q32;q13) is a recurrent chromosomal translocation reported in a variety of B-cell leukemias and lymphomas, including chronic lymphocytic leukemia (CLL). CLL cases associated with t(14;19) often have atypical morphologic and immunophenotypic features and unmutated immunoglobulin heavy chain (IGH) variable region (V) genes, associated with an aggressive clinical course. We analyzed IGHV somatic mutation status and gene use in 11 patients with t(14;19)-positive CLL. All cases were unmutated, and the IGHV genes in 10 cases showed minimal deviation from germline sequences. In 7 of 11 patients, we found homologous heavy chain rearrangements using IGHV4-39; light chain analysis revealed identical IGKV1-39 use. Corresponding V-(D)-J sequences demonstrated remarkable stereotypy of the immunoglobulin heavy and kappa light chain complementarity determining region 3 (H/K CDR3) genes. These findings raise the possibility that specific antigen drive is involved in the clonal development and/or selection of t(14;19)(q32;q13)-positive CLL cells. Our findings support the hypothesis that stimulatory signals through specific antigen receptors may promote the expansion of either CLL precursor cells or CLL clones that harbor distinct chromosomal abnormalities., (Copyright © 2010 UICC.)

The t(14;19)(q32;q13) involving the IGH@ and BCL3 loci is an infrequent cytogenetic abnormality detected in B-cell malignancies. We describe the clinicopathologic, cytogenetic, and molecular genetic characteristics of 14 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with t(14;19)(q32;q13). All patients (10 men and 4 women) had lymphocytosis; 10 had lymphadenopathy. Blood and bone marrow lymphocytes were predominantly small, but cytologically and immunophenotypically atypical. In all cases, t(14;19) was found in the neoplastic stem line; it was the sole abnormality in 4. Ten cases showed additional cytogenetic abnormalities, including trisomy 12 in 9 and complex karyotypes in 7. Fluorescence in situ hybridization demonstrated IGH@/BCL3 fusion gene in all cases. In all cases, the IGHV genes were unmutated, but only 7 expressed ZAP70. Seven cases preferentially used IGHV4-39. Our results indicate that t(14;19)(q32;q13) identifies a subset of CLL/SLL with distinctive clinicopathologic and genetic features. Furthermore, t(14;19) may represent an early, possibly primary, genetic event.

We previously reported a recurrent t(3;8)(q26;q24) translocation involving EVI1 in five patients with myelodysplastic syndrome or acute myeloid leukemia. Here we report the same structural abnormality in a case of chronic myeloid leukemia in blast phase. The t(3;8)(q26;q24) occurred several months after the initial diagnosis of chronic myeloid leukemia, while the patient was being treated with a tyrosine kinase inhibitor. We confirmed rearrangement of EVI1 by fluorescence in situ hybridization assay using a dual-color break-apart probe set that spans the EVI1 region. Our findings demonstrate that, similar to other recurrent translocations involving 3q26, such as t(3;3) and t(3;21), the t(3;8)(q26;q24) is implicated not only in myelodysplastic syndrome and acute myeloid leukemia, but also in progression of chronic myeloid leukemia. These findings extend the known disease spectrum associated with this cytogenetic aberration.

The t(2;14)(p16;q32) has been reported previously in only 12 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The clinicopathologic features have been incompletely described. We describe 6 new cases of CLL/SLL with t(2;14)(p16;q32). All had marrow involvement, 4 had absolute lymphocytosis, 4 had lymphadenopathy, and 3 had hepatosplenomegaly. All showed atypical lymphocyte morphologic features with plasmacytoid differentiation and irregular nuclei; 3 had increased prolymphocytes. Flow cytometry demonstrated typical immunophenotypes in 5 and an atypical immunophenotype in 1. All expressed ZAP70; 5 assessed showed unmutated IgV(H) genes. Karyotyping identified t(2;14)(p16;q32) as the sole abnormality in 1, primary abnormality in 2, and part of a complex karyotype in 3. Fluorescence in situ hybridization analysis revealed BCL11A/IgH rearrangement in all. After chemotherapy, 3 patients died of disease and 3 were alive with disease (median follow-up, 80 months). We conclude that CLL/SLL with t(2;14) (p16;q32) and BCL11A/IgH rearrangement is characterized by atypical morphologic features and unmutated IgV(H) genes.

To determine if therapy-related acute myeloid leukemia (t-AML) with t(8;21)(q22;q22) [t-AML-t(8;21)] harbors similar characteristic clinicopathologic features as de novo AML-t(8;21) (q22;q22), we studied 13 cases of t-AML-t(8;21) and 38 adult cases of de novo AML-t(8;21) diagnosed and treated at our hospital (1995-2008). Of 13 t-AML-t(8;21) cases, 11 had previously received chemotherapy with or without radiation for malignant neoplasms and 2 received radiation alone. The median latency to t-AML onset was 37 months (range, 11-126 months). Compared with patients with de novo AML-t(8;21), patients with t-AML-t(8;21) were older (P = .001) and had a lower WBC count (P = .039), substantial morphologic dysplasia, and comparable CD19/CD56 expression. The AML1-ETO (RUNX1-RUNX1T1) fusion was demonstrated in all 10 cases assessed. Class I mutations analyzed included FLT3 (0/10 [0%]), RAS (0/10 [0%]), JAK2 V617 (0/11 [0%]), and KIT (4/11 [36%]). With a median follow-up of 13 months, 10 patients with t-AML-t(8;21) died; the overall survival was significantly inferior to that of patients with de novo AML-t(8;21) (19 months vs not reached; P = .002). These findings suggest that t-AML-t(8;21) shares many features with de novo AML-t(8;21)(q22;q22), but affected patients have a worse outcome.

Chromosomal translocations that involve MYC, characteristic of Burkitt lymphoma, are rare in chronic lymphocytic leukaemia (CLL). We report the clinical, morphological, immunophenotypic, cytogenetic and molecular genetic features of eight CLL cases with MYC rearrangement. The patients, five men and three women (median age, 71 years) had bone marrow involvement and an absolute peripheral blood lymphocytosis; five had lymphadenopathy; seven had splenomegaly. Prolymphocytes were increased (>/=10%) in all cases. Six cases were classified as CLL with increased prolymphocytes (CLL/PL; prolymphocytes 10-55%), and two were classified as CLL in prolymphocytic transformation (CLL/PT; prolymphocytes >55%). All cases co-expressed CD5, CD19, and CD23; five of eight expressed ZAP-70. Of seven cases tested, four had mutated and three had unmutated IGHV genes. Conventional cytogenetic studies demonstrated t(8;14)(q24.1;q32) in five cases, t(8;22)(q24.1;q11) in two cases, and t(2;8)(p12;q24.1) in one case. Seven cases contained additional chromosomal abnormalities. All patients received combination chemotherapy. Two developed Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphomas (DLBCL) that were clonally unrelated to the CLL. At follow-up, two patients are alive, four died of underlying disease, one died of EBV-associated DLBCL, and one died of an unrelated cancer. In summary, MYC rearrangement, which occurs rarely in CLL patients, is associated with increased prolymphocytes, complex cytogenetic abnormalities, and a poor prognosis.

EVI is a proto-oncogene that is activated in acute myeloid leukemia with chromosomal rearrangements that map to chromosome 3q26. We previously reported the clinicopathologic features of five cases of acute myeloid leukemia carrying t(3;8)(q26;q24). Using fluorescence in situ hybridization analysis, we demonstrate in the current study that the breakpoint on chromosome 3 is at EVI1/MDS1, and the breakpoint on chromosome 8 is just distal to the PVT1 oncogene homolog, a C-MYC activator in mice. The breakpoint on chromosome 8 was detected between the components of the LSI MYC dual-color break-apart rearrangement probe. Reverse-transcriptase polymerase chain reaction assay showed expression of EVI1 in all four cases analyzed, and DNA sequence analysis confirmed the findings. Reverse transcriptase polymerase chain reaction assay also demonstrated the expression of PVT1 and C-MYC in all four cases assessed. Western blot analysis detected EVI1 in one case analyzed. We conclude that the t(3;8)(q26;q24) results in deregulated EVI1 expression, similar to other balanced or unbalanced chromosomal translocations involving chromosome 3q26.

The t(14;19)(q32;q13), involving the BCL3 locus at chromosome 19q13 and the immunoglobulin heavy chain gene at 14q32, is a rare recurrent cytogenetic abnormality identified in B-cell neoplasms, most of which have been classified as chronic lymphocytic leukaemia (CLL) in the literature. We describe the clinicopathological, immunophenotypic and cytogenetic findings in seven patients with B-cell neoplasms associated with t(14;19)(q32;q13). There were five men and two women, with a median age of 48 years (range 33-68). All had absolute lymphocytosis, six had lymphadenopathy, and one had splenomegaly. Lymphocytes in blood and bone marrow aspirate smears were predominantly small and cytologically atypical. Flow cytometric immunophenotyping showed an atypical immunophenotype with low CLL scores. The growth pattern in bone marrow biopsy specimens was interstitial to diffuse; immunohistochemical stains were positive for bcl3 and negative for cyclin D1. Lymph node biopsy specimens of two patients revealed total architectural effacement by neoplasm with proliferation centres. In addition to t(14;19), cytogenetic studies demonstrated trisomy 12 in five patients. These results suggest that B-cell neoplasms with the t(14;19)(q32;q13) present frequently as leukaemia composed of small B-lymphocytes and share many features with CLL. However, these neoplasms also differ from CLL cytologically and in their immunophenotype.

Context: Sarcomas are rare, numerous in type, and often difficult to definitively classify. Work in the last 2 decades has revealed that a significant subset of sarcomas are associated with specific chromosomal translocations producing chimeric (fusion) genes that play a role in the sarcomas' biology and are helpful in their differential diagnosis., Objective: To briefly review the sarcomas associated with specific translocations presenting Ewing sarcoma and synovial sarcoma as archetypes and to further explain how cytogenetic and molecular biologic approaches are being used in the diagnosis of sarcomas., Data Sources: This work is based on a selected review of the relevant medical and scientific literature and our extensive experience with molecular testing in sarcomas., Conclusions: In addition to, and complementing, the traditional diagnostic methods of examination of hematoxylin-eosin stained slides, immunohistochemistry, and sound clinical-pathologic correlation, additional cytogenetic and molecular biologic methods are being increasingly utilized and relied on in sarcoma pathology. These methods include chromosomal karyotyping, fluorescence in-situ hybridization, spectral karyotyping, and polymerase chain reaction- based methods for demonstrating specific chromosomal translocations and fusion genes. Understanding the basis of these methods and their application is critical to better provide accurate and validated specific diagnoses of sarcomas.

We identified a reciprocal translocation between chromosomes 3 and 8, with breakpoints at bands 3q26 and 8q24, in five patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The t(3;8)(q26;q24) was the sole cytogenetic aberration in two patients, was associated with trisomy 13 in one patient, and occurred with monosomy 7 in two patients. In three patients, the AML or MDS developed 36, 52, and 57 months following chemotherapy for soft tissue sarcoma, mantle cell lymphoma, and diffuse large B-cell lymphoma, respectively; in these three patients, the neoplasms were considered to be therapy-related. All five patients displayed marked trilineage dysplasia and variable degrees of cytopenias, with marked thrombocytosis noted in one patient and a normal platelet count in another patient. All patients were treated with combination chemotherapy; at writing, four were still alive and one had died during a follow-up period ranging from 1 to 16 months. We conclude that the t(3;8)(q26;q24) is a recurrent translocation associated with therapy-related MDS/AML or de novo AML, and is frequently associated with monosomy 7.

Acute myeloid leukemia (AML) with the t(8;21) (q22;q22) creating the AML1-ETO fusion gene is a distinct type of AML generally associated with a favorable prognosis. The clinicopathologic features of AML carrying variant t(8;21) are less well characterized. We report 4 cases of AML characterized by ins(8;21)(q22;q22q22), t(1;21;8)(q25;q22;q22), t(8;11;21)(q22;q13;q22), and t(4;21;8;12)(q31.3;q22;q22;q15), respectively. Fluorescence in situ hybridization or reverse transcriptase-polymerase chain reaction assay confirmed the presence of AML1-ETO or its transcripts in 3 cases assessed. Each neoplasm had morphologic characteristics of AML associated with the t(8;21). The blasts in 2 cases expressed CD19. All patients were treated with combination chemotherapy and are in complete remission, despite 2 relapses in 1 patient, with a follow-up period ranging from 8 to 46 months. We conclude that cases of AML with variant t(8;21) display morphologic, immunophenotypic, and clinical features similar to classical cases. A combination of conventional cytogenetic, and molecular analyses allows identification of these variants.

We identified 14 B-cell neoplasms with concurrent t(14;18) and chromosome 8q24 or c-MYC translocations shown by conventional cytogenetics or fluorescence in situ hybridization analysis. All cases assessed by conventional cytogenetics had a complex karyotype. There were 10 men and four women, with a median age of 55 years (range, 29-72). None of these patients had a history of follicular lymphoma. The biopsy specimens were obtained from bone marrow, lymph node, and extranodal sites. Morphologically, nine neoplasms had features of Burkitt or atypical Burkitt lymphoma/leukemia and three were diffuse large B-cell lymphoma with high-grade cytologic features. The remaining two cases were plasmablastic myeloma and low-grade B-cell lymphoma, respectively. All cases expressed BCL-2. The proliferation index assessed by using Ki-67 (MIB1) was 5% in the low-grade B-cell lymphoma, 80% in the plasmablastic myeloma, 90-95% in three cases of diffuse large B-cell lymphoma, and ranged from 90 to >99% in most Burkitt and atypical Burkitt neoplasms. The patient with low-grade B-cell lymphoma was treated with rituximab. All other patients received intensive combination chemotherapy. Two of these patients underwent bone marrow transplantation, and one patient received radiation therapy in addition to transplantation. The median follow-up period was 9 months (range, 3-81). In all, 10 patients died with a median survival of 9 months (range, 3-81). We conclude that most B-cell lymphomas with concurrent t(14;18) and 8q24/c-MYC translocations fall within the morphologic spectrum of diffuse large B-cell and Burkitt lymphoma. These neoplasms are high-grade and are associated with a poor prognosis. However, this combination of molecular abnormalities can also rarely occur in other neoplasms, such as the cases of low-grade B-cell lymphoma and plasmablastic myeloma in this study.

The authors report a unique translocation in a patient with M7 acute myeloid leukemia and review the literature. A 22-month-old girl without Down syndrome was diagnosed with acute myeloid leukemia, subtype M7 (AML-M7), and died with relapsed disease following bone marrow transplantation. Tumor cells were evaluated using cytogenetics (including spectral karyotyping), immunohistochemistry, and flow cytometry. The patient was found to have a previously unreported complex translocation as follows: 50,XX,der(1)t(1;5)(p36?.1;p15?.1),del(5)(p15?.1), +6,+der(6;7)(?;?),der(7)t(6;7)(?;p22)[2],der(9)t(6;9) (?;p21)t(9;14)(q34;q11.2-q13),+10,t(12;16)(p13;q24),-14[2], del(14)(q13)[2],+der(19)t(1;19)(?;p13.3),+22[cp 4]. AML-M7 in non-Down syndrome patients is a rare disease that requires improved prognostic markers.