B-cell Lymphoid Neoplasms Research Articles

Post-transplant lymphoproliferative disorders: a working classification

Categorization of the post-transplant lymphoproliferative disorders (PTLD) is essential because of their diverse clinical, histopathologic, immunophenotypic and genotypic nature. None of the well-established classifications address all of the types of PTLD that are now recognized. For that reason, a working classification of the PTLD was developed based on the preceding classifications, the PTLD literature and a review of adult PTLD. Besides recognizing plasmacytic hyperplasia in some post-transplant patients, the working classification includes the following types of PTLD: infectious mononucleosis-like, plasma cell rich, polymorphic, monomorphic, multiple myeloma-like, T-cell type, Hodgkin's disease-like, composite and not otherwise specified. Rare patients may also have lymphoid neoplasms that do not fall into any of these categories such as small B-cell lymphoid neoplasms. Criteria for use of this working classification require histopathology at a minimum and, in many cases, at least some ancillary studies. Epstein-Barr virus (EBV) positivity may aid in the recognition of a PTLD in some circumstances; however, it is not an absolute requirement for the diagnosis of a PTLD. EBV negative PTLD exist and have some characteristic features. Some, but not all, of these EBV negative cases, however, may represent coincidental lymphoid neoplasms that are not directly related to the patient's iatrogenic immunosuppression. Finally, a model of PTLD is presented which illustrates the relationship between histopathology, clonality, associated non-clonal T-cells, secondary genotypic abnormalities and responsiveness to a therapeutic decrease in immunosuppression.

Significance of Rearrangement of the BCL6 Gene in B-Cell Lymphoid Neoplasms

Chromosomal translocations involving 3q27 are among the most common recurring translo-cations in non-Hodgkin's lymphoma (NHL) of B-cell phenotype. Molecular cloning of junctional areas of the translocations resulted in isolation of the BCL6 gene adjacent to the breakpoint cluster on 3q27. The gene encodes a zinc-finger transcription factor which is expressed in nuclei of germinal center B-cells. Rearrangement of BCL6 was observed in 6.4 to 14.3% of follicular lymphomas and 28.6 to 35.5% of diffuse large cell lymphomas; regarding the latter, a Japanese series showed a lower incidence. Survival curves suggested that NHL carrying rearrangement of BCL6 and lacking that of BCL2 is curable by chemotherapy. Detailed analysis of the vicinity of translocations showed that the 5′ untranslated region of BCL6 was replaced by heterogeneous promoters not only from immunoglobulin genes but also from many previously uncharacterized loci. Bcl-6 protein ia expressed in NHL of follicular center B-cell origin, independently of the presence or absence of BCL6 rearrangement. At present, limited information is available about the functional consequences of the rearrangements and, in particular, about their ultimate implications for lymphomagenesis.

The morphologic spectrum of non-Hodgkin's lymphomas with BCL1/cyclin D1 gene rearrangements.

BCL1/PRAD1 gene rearrangements involving the cyclin D1 gene are a feature of about 70% of centrocytic/mantle-cell lymphomas (CC/MCL) but are identified in only a small proportion of other B-cell non-Hodgkin's lymphomas. Of 37 lymphomas found to have BCL1/cyclin D1 (PRAD1, CCND1) gene rearrangements, 30 fit the morphologic and immunophenotypic criteria for typical CC/MCL. Seven cases with morphologic features atypical for CC/MCL were identified. CD5+ monoclonal B cells were documented in all these cases. Six cases were subsequently stained for cyclin D1 protein, and all showed nuclear positivity. Five cases had variably sized foci of cells with moderately abundant pale cytoplasm resembling parafollicular/monocytoid B cells, marginal zone cells, hairy cells, or even proliferation centers. Transformed-appearing cells were also present in some lymphomas. In one case, striking follicular colonization created a markedly nodular growth pattern mimicking a follicular lymphoma. A sixth case had a marked predominance of small, round lymphocytes at some sites, mimicking a small lymphocytic lymphoma. Five of these six cases also had areas more typical of CC/MCL. The seventh case was a CD5-positive splenic marginal zone-like lymphoma (SMZL) with plasmacytic differentiation and circulating villous lymphocytes consistent with a splenic lymphoma with villous lymphocytes (SLVL). These cases illustrate the morphologic spectrum of small B-cell lymphoid neoplasms that have BCL1/cyclin D1 gene rearrangements and overexpression of cyclin D1. Despite the BCL1 translocation and cyclin D1 overexpression, the splenic lymphoma with plasmacytic differentiation was definitely not a CC/MCL and fit the clinicopathologic entity of SMZL/SLVL. The other six cases are best considered CC/MCL variants based on a combined morphologic, immunophenotypic, and genotypic evaluation. Genotypic or immunophenotypic studies to identify cyclin D1 rearrangements and overexpression, although not pathognomonic, are useful in recognizing these variant CC/MCL cases, which can mimic almost any of the other well-described but more indolent low-grade B-cell lymphomas and leukemias. Some of the variant CC/MCL cases had features in common with the CD5+ cyclin D1+ SMZL/SLVL, suggesting a possible relationship between these two otherwise distinct entities.

Induction of cell surface interleukin 2 receptor alpha chain expression on non-T lymphoid leukemia cells

We examined nine cases of adult non-T lymphoid leukemia to investigate the cell surface inducibility of interleukin 2 receptor α chain (IL-2Rα) and β chain (IL-2Rβ) after in vitro culture with and without recombinant human interleukin-1β (rhIL-1β). Induction of IL-2Rα was observed in four of six cases with precursor B-cell acute lymphoblastic leukemia (pre-B ALL) and in all of three cases with B-cell mature lymphoid neoplasm (two chronic lymphocytic leukemia and one leukemic phase of non-Hodgkin's lymphoma). All of the IL-2Rα-inducible cases could express this spontaneously even without rhIL-1β, while IL-2Rβ did not appear on leukemic cells from any of the cases tested. IL-2Rα-inducible pre-B ALL cases displayed stem cell antigen CD34 and induced myeloid-associated antigen CD13 simultaneously. These results suggest that IL-2Rα but not IL-2Rβ is easily inducible in certain cases of mature B-cell lymphoid neoplasm and pre-B ALL with immature characteristics.

Lymphoblast Purine Pathway Enzymes in B-Cell Acute Lymphoblastic Leukemia

Activities of enzymes of the purine metabolic pathway, adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'-nucleotidase (5'-N), were investigated in the lymphoblasts of a patient with B-cell acute lymphoblastic leukemia. These lymphoblasts exhibited increased ADA activity and diminished activities of both PNP and 5'N' as compared to normal lymphocytes as well as non-T, non-B leukemia cells. This enzymatic pattern is identical to that which has been described in T-cell leukemic lymphoblasts and differs from that which has been observed in the malignant cells of undifferentiated B-cell lymphomas. These data suggest that there is biochemical heterogeneity within the spectrum of B-cell malignancies. Furthermore, inhibitors of ADA may be of use in those B-cell lymphoid neoplasms that exhibit increased ADA activity.

Lymphoblast purine pathway enzymes in B-cell acute lymphoblastic leukemia

Activities of enzymes of the purine metabolic pathway, adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5′- nucleotidase (5′-N), were investigated in the lymphoblasts of a patient with B-cell acute lymphoblastic leukemia. These lymphoblasts exhibited increased ADA activity and diminished activities of both PNP and 5′N' as compared to normal lymphocytes as well as non-T, non-B leukemia cells. This enzymatic pattern is identical to that which has been described in T-cell leukemic lymphoblasts and differs from that which has been observed in the malignant cells of undifferentiated B-cell lymphomas. These data suggest that there is biochemical heterogeneity within the spectrum of B-cell malignancies. Furthermore, inhibitors of ADA may be of use in those B-cell lymphoid neoplasms that exhibit increased ADA activity.