William G. Finn

The clinical significance of CD10 antigen expression in diffuse large B-cell lymphoma

The clinical significance and prognostic value of CD10 in de novo diffuse large B-cell lymphoma (DLBCL) is largely unknown. We retrospectively studied 19 men and 9 women based on the following criteria: (1) DLBCL with no evidence of concomitant or antecedent follicular lymphoma; (2) available flow cytometric immunophenotyping data, including CD10 status; (3) older than 15 years; (4) specific exclusion of high-grade, Burkitt-like lymphoma; and (5) exclusion of primary cutaneous DLBCL. When available, clinical data at diagnosis, including components of the international prognostic index, were reviewed. Eleven cases were CD10+, and 17 were CD10-. There was no significant difference between the CD10+ and CD10- groups in age, sex, stage, performance status, extranodal involvement, or serum lactate dehydrogenase levels at diagnosis. However, in the 26 cases for which follow-up data were available, the CD10+ group displayed a shorter overall survival than the CD10- group (8 vs 30 months). Although the clinical findings at diagnosis are similar in CD10+ and CD10- DLBCL, CD10 expression is associated with shortened overall survival. Therefore, our data suggest CD10 expression may have prognostic importance in adults with de novo DLBCL.

Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages

BackgroundInterleukin-33 is a member of the IL-1 cytokine family whose functions are mediated and modulated by the ST2 receptor. IL-33-ST2 expression and interactions have been explored in mouse macrophages but little is known about the effect of IL-33 on human macrophages. The expression of ST2 transcript and protein levels, and IL-33-mediated effects on M1 (i.e. classical activation) and M2 (i.e. alternative activation) chemokine marker expression in human bone marrow-derived macrophages were examined.ResultsHuman macrophages constitutively expressed the membrane-associated (i.e. ST2L) and the soluble (i.e. sST2) ST2 receptors. M2 (IL-4 + IL-13) skewing stimuli markedly increased the expression of ST2L, but neither polarizing cytokine treatment promoted the release of sST2 from these cells. When added to naïve macrophages alone, IL-33 directly enhanced the expression of CCL3. In combination with LPS, IL-33 blocked the expression of the M2 chemokine marker CCL18, but did not alter CCL3 expression in these naive cells. The addition of IL-33 to M1 macrophages markedly increased the expression of CCL18 above that detected in untreated M1 macrophages. Similarly, alternatively activated human macrophages treated with IL-33 exhibited enhanced expression of CCL18 and the M2 marker mannose receptor above that detected in M2 macrophages alone.ConclusionsTogether, these data suggest that primary responses to IL-33 in bone marrow derived human macrophages favors M1 chemokine generation while its addition to polarized human macrophages promotes or amplifies M2 chemokine expression.

Secondary Abnormalities of Chromosome 6q in B‐Cell Chronic Lymphocytic Leukemia: A Sequential Study of Karyotypic Instability in 51 Patients

Although karyotypic abnormalities are well documented in B‐cell chronic lymphocytic leukemia (B‐CLL), few sequential cytogenetic studies have been done. In this study, peripheral blood lymphocytes from fifty‐one patients with B‐CLL were sequentially karyotyped over a mean interval of 13.8 months (range, one to 51 months). Cytogenetic clones were detected in 33/51 patients (66%) on initial study, including 17 patients with structural abnormalities of chromosome 13q14, and three patients with trisomy 12. Karyotypic evolution was documented in 22/51 patients (43%). The most common secondarily acquired chromosome aberrations were structural abnormalities of the long arm of chromosome 6 involving the region of 6q21‐q24 (six patients). Four patients each had acquired structural abnormalities of 1q, 3p, 12q, and 13q. Disease progression, as measured by advance in Rai stage or death from the disease, was observed more often in the clonal evolution group than in the karyotypically stable group (11/22 vs. 5/29; P = 0.017). Patients with secondary abnormalities of 6q had a significantly decreased progression‐free survival interval compared with other patients in the study (P = .023). The authors conclude that clonal karyotypic evolution is common in B‐CLL, and that clonal evolution correlates with clinical disease progression. Furthermore, the poor outcomes previously attributed to CLL with 6q abnormalities may be related to the clonal acquisition of these abnormalities over time. Future studies should focus on the relevant genetic events underlying the clinical progression observed with karyotypic evolution of B‐CLL. Am. J. Hematol. 59:223–229, 1998.

FINE: Fisher Information Nonparametric Embedding

We consider the problems of clustering, classification, and visualization of high-dimensional data when no straightforward Euclidean representation exists. In this paper, we propose using the properties of information geometry and statistical manifolds in order to define similarities between data sets using the Fisher information distance. We will show that this metric can be approximated using entirely nonparametric methods, as the parameterization and geometry of the manifold is generally unknown. Furthermore, by using multidimensional scaling methods, we are able to reconstruct the statistical manifold in a low-dimensional Euclidean space; enabling effective learning on the data. As a whole, we refer to our framework as Fisher information nonparametric embedding (FINE) and illustrate its uses on practical problems, including a biomedical application and document classification.

Lymphocytic Mastitis and Diabetic Mastopathy: A Molecular, Immunophenotypic, and Clinicopathologic Evaluation of 11 Cases

Lymphocytic mastitis and diabetic mastopathy are uncommon fibroinflammatory breast diseases. The lesions seen in these entities are unique in that the associated lymphoid infiltrates are composed of predominantly B cells. In addition, B-cell lymphoepithelial lesions, a finding commonly associated with extranodal marginal zone B-cell/mucosa-associated lymphoid tissue (MALT) lymphomas, are also often present in lymphocytic mastitis and diabetic mastopathy. Although the clinical and immunomorphologic features are well characterized, the clonality of the B-cell infiltrate and the lymphomatous potential of lymphocytic mastitis and diabetic mastopathy have not been emphasized in the literature. We evaluated 11 cases of lymphocytic mastitis/diabetic mastopathy for immunoglobulin heavy chain gene rearrangement and correlated the findings with all available clinical data. A longstanding history of Type I diabetes mellitus was present in seven patients. One nondiabetic patient had Sjogren’s syndrome, and two patients had no history of diabetes mellitus or other autoimmune disease. Clinical data were unavailable for one patient. B-cell–predominant lymphoid infiltrates were seen in all cases, and B-cell lymphoepithelial lesions were found in five. No evidence of a B-cell clone was found in any of the 11 cases by appropriately controlled immunoglobulin heavy chain gene rearrangement studies, and none of the patients developed lymphoma during follow-up intervals ranging from 2–126 months. These findings suggest that despite the presence of B-cell–predominant lymphoid infiltrates and lymphoepithelial lesions, lymphocytic mastitis and diabetic mastopathy do not appear to be associated with an increased risk for lymphoma.

Waldenström Macroglobulinemia Caused by Extranodal Marginal Zone B-Cell Lymphoma A Report of Six Cases

Waldenström macroglobulinemia (WM) and its associated hyperviscosity syndrome (HVS) are generally caused by lymphoplasmacytoid lymphoma or other small B-cell lymphoproliferative disorders. WM associated with extranodal marginal zone B-cell-mucosa-associated lymphoid tissue lymphoma (EMZL/MALT-type) has not been emphasized. We describe 4 men and 2 women (age, 40-79 years) with clinical and laboratory manifestations of WM and EMZL/MALT-type involving one or more sites: lung, pericardium/pleura, ocular adnexa, nasopharynx, minor salivary gland, glossopharyngeal fold, skin, and stomach. The following immunophenotypic patterns were observed: CD20+, 6; CD43+, 3; kappa light chain restriction, 5; and lambda light chain restriction, 1. All were negative for CD5, CD10, and cyclin D1 expression. A clonal paraproteinemia was present in each (IgM kappa, 4; IgM lambda, 1; biclonal IgM kappa/IgA kappa, 1). All 4 patients tested had elevated plasma viscosity; clinical HVS occurred in 3, and 2 required emergency plasmapheresis. These findings suggest that EMZL/MALT-type can cause WM and that the laboratory evaluation of EMZL/MALT-type should include serum protein electrophoresis/immunofixation, and plasma viscosity measurements and urine immunofixation in select cases. EMZL/MALT-type should be considered in the differential diagnosis in patients with clinicopathologic features of WM.

Expansions of clonal and oligoclonal T cells in B‐cell chronic lymphocytic leukemia are primarily restricted to the CD3+CD8+ T‐cell population

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of mature-appearing clonal B cells exhibiting coexpression of CD5 and CD23. In addition to the accumulation of neoplastic B cells, numerous T-cell abnormalities also occur in B-CLL patients. In this study, the presence, and distribution within the T-cell subsets, of clonal/oligoclonal T cells was studied. Multicolor flow cytometric techniques were employed using combinations of anti-CD3, anti-CD4, and anti-CD8 antibodies coupled with antibodies specific for V(alpha) and V(beta) T-cell receptor (TCR) epitopes. Molecular studies of TCR gene sequences were done to confirm the presence of clonal/oligoclonal T-cell populations. In the flow cytometric studies, examination of V(alpha)/V(beta)expression found evidence of clonal/oligoclonal expansion in 9 of 19 patients studied. In eight of the nine patients, the expansions were restricted to the CD3(+)CD8(+) cell population. Molecular analyses were performed in 16 patients, 12 of whom showed a clonal or oligoclonal pattern. Of the four patients who were negative in the molecular analyses, all demonstrated flow cytometric evidence of clonal/oligoclonal expansions. Thus, when the flow cytometric and molecular analyses were considered together, all 16 patients for whom parallel analyses were done showed evidence of clonal/oligoclonal expansions. These results confirm previous work demonstrating that the majority of B-CLL patients harbor clonal/oligoclonal expansions within the T-cell population. Additionally, based on the relative numbers of cells expressing specific V(alpha) or V(beta)epitopes, these results show that these expansions occur primarily within the CD3(+)CD8(+) T-cell population.

Analysis of clinical flow cytometric immunophenotyping data by clustering on statistical manifolds: Treating flow cytometry data as high‐dimensional objects

Clinical flow cytometry typically involves the sequential interpretation of two‐dimensional histograms, usually culled from six or more cellular characteristics, following initial selection (gating) of cell populations based on a different subset of these characteristics. We examined the feasibility of instead treating gated n‐parameter clinical flow cytometry data as objects embedded in n‐dimensional space using principles of information geometry via a recently described method known as Fisher Information Non‐parametric Embedding (FINE).

Immunomodulator agent-related lymphoproliferative disorders

The recent development of inhibitors of key immune response proteins has revolutionized the therapy of autoimmune diseases; these immunomodulator agents include monoclonal antibodies and receptor antagonists. However, as with all therapies, these new agents are not without side effects and complications. In particular, anti-tumor necrosis factor alpha (TNFα) agents have been reported to be associated with an increased incidence of lymphoproliferative disorders, infections, and vasculitis. We evaluated the clinicopathological features of 18 cases of immunomodulator agent-related lymphoproliferative disorders (IAR-LPD) from several institutions. These included 6 cases of B-cell lymphoma, 2 cases of T-cell lymphoma, 3 cases of classical Hodgkin lymphoma, and 7 atypical lymphoid proliferations that did not fulfill diagnostic criteria for lymphoma; two of the latter regressed after discontinuation of the immunomodulator agent therapy. All eight lymphoma patients with available information had also received prior chemotherapy (methotrexate or 6-mercaptopurine). EBV was strongly associated with the B-cell and classical Hodgkin lymphomas. This case series illustrates that a broad range of lymphoid proliferations can occur after immunomodulator agent therapy and that these immunomodulator agent-related lymphoproliferative disorders have considerable overlap with other well-defined lymphoproliferative diseases associated with iatrogenic immunosuppression. Further study is warranted to evaluate how these therapies interact with other immunosuppressive agents and the underlying abnormal immune system to enhance the development of lymphomas and atypical lymphoid proliferations.

Cerebrospinal Fluid Involvement in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive neoplasm that is incurable by standard therapy. Patients often present with high-stage disease (Stages III–IV) and frequently have involvement at multiple extranodal sites. Although the gastrointestinal tract, spleen, lung, pleura, bone marrow, and peripheral blood are among the most commonly involved tissues, MCL may also disseminate to so-called sanctuary sites including the central nervous system. Despite this, current clinical evaluations do not routinely include assessment of the cerebrospinal fluid (CSF) for lymphomatous infiltrates at presentation, and moreover, only few authors have specifically examined CSF involvement in MCL. In this study, we reviewed the medical records of 108 patients with MCL seen at three centers over a 5-year period to determine the rate of CSF sampling and the frequency of CSF involvement by MCL. The clinical and cytologic characteristics associated with CSF involvement were also studied. Central nervous system (CNS) signs and/or symptoms prompted CSF sampling in 25/108 patients (23%). Specific radiographic abnormalities were present in 9/25 patients (36%). CSF involvement by MCL was identified in 10 of the 25 CSF-sampled patients (40%) by morphology (3 patients), flow cytometry alone (1 patients), or both (6 patients). The CSF-positive cases included two blastoid variants. The CSF cytology of the nine morphologically positive cases was pleomorphic, and prominent cytoplasmic granules were observed in two cases. The overall rate of CSF involvement by MCL among the cohort was 9%, which is comparable to that reported in other selected studies examining this issue.