Differential expression of NF-kappaB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism.

Mucosa-associated lymphoid tissue (MALT) lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the nuclear factor (NF)-kappaB pathway. Gastric MALT lymphomas harboring such translocations usually do not respond to Helicobacter pylori eradication, while most of those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 21 MALT lymphomas (13 translocation-positive, 8 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-kappaB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions have shown that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-kappaB target genes, particularly toll like receptor (TLR)6, chemokine, CC motif, receptor (CCR)2, cluster of differentiation (CD)69 and B-cell CLL/lymphoma (BCL)2, while translocation-negative cases were featured by active inflammatory and immune responses, such as interleukin-8, CD86, CD28 and inducible T-cell costimulator (ICOS). Separate analyses of the genes differentially expressed between translocation-positive and -negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10-mediated NF-kappaB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors.

Continual monitoring of intraepithelial lymphocyte immunophenotype and clonality is more important than snapshot analysis in the surveillance of refractory coeliac disease.

OBJECTIVE: An aberrant immunophenotype and monoclonality of intraepithelial lymphocytes (IELs) are frequently found in refractory coeliac disease (RCD). However, the utility of continual monitoring of IEL immunophenotype and clonality in the surveillance of RCD remains to be studied. DESIGN: The diagnostic and follow-up biopsies from 33 patients with CD, 7 with suspected RCD, 41 with RCD and 20 with enteropathy-associated T cell lymphoma (EATL) (including 11 evolved from RCD) were investigated by CD3epsilon/CD8 double immunohistochemistry and PCR-based clonality analysis of the rearranged T cell receptor (TCR) genes. RESULTS: An aberrant immunophenotype (CD3epsilon(+)CD8(-) IELs > or =40%) and monoclonality were detected occasionally in CD biopsies, either transiently in patients with CD not compliant with a gluten-free diet or in those who subsequently developed suspected RCD, RCD or EATL. In contrast, the aberrant immunophenotype and monoclonality were found in 30 of 41 (73%) and 24 of 37 (65%) biopsies, respectively, at the time of RCD diagnosis. Among the patients with RCD who did not show these abnormalities in their diagnostic biopsies, 8 of 10 (80%) and 5 of 11 (45%) cases gained an aberrant immunophenotype and monoclonality, respectively, during follow-up. Irrespective of whether detected in diagnostic or follow-up biopsies, persistence of both abnormalities was characteristic of RCD. Importantly, the presence of concurrent persistent monoclonality and aberrant immunophenotype, especially > or =80% CD3epsilon(+)CD8(-) IELs, was a strong predictor of EATL development in patients with RCD (p=0.001). CONCLUSIONS: Continual monitoring of both immunophenotype and clonality of IELs is more important than snapshot analysis for RCD diagnosis and follow-up, and could provide a useful tool for surveillance of patients at risk of EATL.

A20 deletion is associated with copy number gain at the TNFA/B/C locus and occurs preferentially in translocation-negative MALT lymphoma of the ocular adnexa and salivary glands.

The genetic basis of MALT lymphoma is largely unknown. Characteristic chromosomal translocations are frequently associated with gastric and pulmonary cases, but are rare at other sites. We compared the genetic profiles of 33 ocular adnexal and 25 pulmonary MALT lymphomas by 1 Mb array-comparative genomic hybridization (CGH) and revealed recurrent 6q23 losses and 6p21.2-6p22.1 gains exclusive to ocular cases. High-resolution chromosome 6 tile-path array-CGH identified NF-kappaB inhibitor A20 as the target of 6q23.3 deletion and TNFA/B/C locus as a putative target of 6p21.2-22.1 gain. Interphase fluorescence in situ hybridization showed that A20 deletion occurred in MALT lymphoma of the ocular adnexa (8/42=19%), salivary gland (2/24=8%), thyroid (1/9=11%) and liver (1/2), but not in the lung (26), stomach (45) and skin (13). Homozygous deletion was observed in three cases. A20 deletion and TNFA/B/C gain were significantly associated (p<0.001) and exclusively found in cases without characteristic translocation. In ocular cases, A20 deletion was associated with concurrent involvement of different adnexal tissues or extraocular sites at diagnosis (p=0.007), a higher proportion of relapse (67% versus 37%) and a shorter relapse-free survival (p=0.033). A20 deletion and gain at TNFA/B/C locus may thus play an important role in the development of translocation-negative MALT lymphoma.

Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 and lymphoproliferative disorders.

Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is a recent addition to the list of human viruses that are directly associated with lymphoproliferative disorders. KSHV was first shown to be involved in multicentric Castleman disease and primary effusion lymphoma (PEL). Subsequently, the virus was identified in solid lymphomas, often of extranodal sites, with morphological and immunophenotypic characteristics similar to those of PEL, and in other lymphoproliferative disorders with heterogeneous clinicopathological presentations. The recent advances in our understanding of the histology, immunophenotype and pathogenesis of these KSHV-associated lymphoproliferative disorders are reviewed.

Haematopathology practice: the commonest problems encountered in a consultation practice.

Although not specifically recognized as a subspecialty of histopathology, haematopathology has a long history of specialist practice in the UK, with a few centres attracting large numbers of referred cases. The specialist nature of haematopathology has been enhanced by the advent of immunohistochemistry and, more recently, molecular genetics, which now play a major role in the diagnosis of haematopoietic and lymphoid neoplasms. Problems encountered by non-specialist pathologists, and reflected in those cases submitted for consultation, include difficulties in the differential diagnosis of certain benign lymphoproliferative disorders from lymphoma and the precise classification of lymphomas which may have an impact on therapeutic decisions. Lymphomas that frequently pose problems include common lesions such as follicular lymphoma and more esoteric disorders such as T-cell/histiocyte-rich large B-cell lymphoma. This review is an attempt to clarify a logical approach to the differential diagnosis of these lesions.

Distinguishing angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified, using morphology, immunophenotype and molecular genetics.

AIMS: To identify distinguishing histological, immunophenotypic and molecular genetic features between angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma (PTL). METHODS: Nodal T-cell lymphomas examined (n =137), included AITL (n = 89), PTL (n = 22), anaplastic large cell lymphoma (n = 16) and 'AITL/PTL indeterminate' (n = 10) with overlapping features between AITL and PTL, showing morphology typical of AITL but lacking follicular dendritic cell expansion. Immunohistochemistry for CD3, CD20, CD21 and CD10, in situ hybridization for Epstein-Barr virus encoded RNA (EBER) and polymerase chain reaction for T-cell and B-cell clonality analysis were performed. RESULTS: Of the AITLs, 74/89 showed typical morphology, whereas 15/89 showed hyperplastic follicles. AITL and 'AITL/PTL indeterminate' showed a polymorphous infiltrate and prominent vascularity in all cases. In both groups, CD10 was present in the majority and clear cells and EBER positivity were specific (but not universal) features lacking in PTL. Detection of T-cell clonality was significantly higher in AITL (90%) compared with PTLu (59%). CONCLUSION: Clear cells and EBV infection (when present) are useful distinguishing features and CD10 a sensitive and specific marker of AITL. Hyperplastic follicles are present in a significant minority of AITL. AITL/PTL indeterminate probably falls within the spectrum of AITL rather than PTL.

Loss of heterozygosity at chromosome 9p21 is a frequent finding in enteropathy-type T-cell lymphoma.

Enteropathy-type T-cell lymphoma (ETL) and ulcerative jejunitis (UJ) are rare disorders often occurring in patients with coeliac disease. The genetic events associated with the accumulation of intraepithelial lymphocytes in coeliac disease and tumour development are largely unknown. Deletions at chromosome 9p21, which harbours the tumour suppressor genes p14/ARF, p15/INK4b, and p16/INK4a, and 17p13, where p53 is located, are associated with the development and progression of lymphomas. To examine whether deletions at 9p21 and 17p13 play a role in ETL, 22 cases of ETL and seven cases of UJ were screened for loss of heterozygosity (LOH) by tissue microdissection and polymerase chain reaction (PCR) analysis for microsatellite markers. Furthermore, p53 and p16 protein expression was examined by immunohistochemistry. In addition, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis for detection of mutations in exons 5-8 of the p53 gene was performed in five cases of ETL and three cases of UJ. LOH was found in at least one microsatellite marker at the 9p21 locus in 8 of 22 (36%) ETLs, but not in UJ. Five of nine (56%) tumours composed of large cells showed LOH at 9p21, as opposed to two of eight (25%) tumours with small- or medium-sized cell morphology. The region spanning the p14/p15/p16 gene locus was most frequently affected (five cases); LOH at these markers coincided with loss of p16 protein expression in all of these cases. p53 overexpression was demonstrated in all ETLs examined and in four of seven cases of UJ. However, no alterations of the p53 gene were detected by LOH or PCR-SSCP analysis. The results of this study show that LOH at chromosome 9p21 is frequent in ETL, especially in tumours with large cell morphology; this finding suggests that gene loss at this locus may play a role in the development of ETL.

Gastric lymphomas: genetics and resistance to H. pylori eradication.

Gastric mucosa associated lymphoid tissue (MALT) lymphoma is a histologically distinct tumour derived from MALT acquired as a result of Helicobacter pylori infection. Eradication of H. pylori causes clinical regression of the lymphoma n 75 % of cases. In seeking to identify those cases resistant to this therapy, and in the interests of further understanding the biology of MALT lymphoma, genetic alterations of MALT lymphomas have been investigated. Three translocations, t(11;18)(q21; q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) are specifically associated with MALT lymphoma and the genes involved have been identified. T(11;18) results in a chimeric fusion between the API2 and MALT1 genes and is specifically associated with gastric MALT lymphomas that do not respond to eradication of H. pylori. T(1; 14) and t(14; 18) deregulate bcl-10 and MALT1 expression respectively. These three chromosomal translocations that involve different genes appear to share common oncogenic properties by targeting the to target the same NFkappaB oncogenic pathway.

Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases.

Neoplasms of histiocytes and dendritic cells are rare, and their phenotypic and biological definition is incomplete. Seeking to identify antigens detectable in paraffin-embedded sections that might allow a more complete, rational immunophenotypic classification of histiocytic/dendritic cell neoplasms, the International Lymphoma Study Group (ILSG) stained 61 tumours of suspected histiocytic/dendritic cell type with a panel of 15 antibodies including those reactive with histiocytes (CD68, lysozyme (LYS)), Langerhans cells (CD1a), follicular dendritic cells (FDC: CD21, CD35) and S100 protein. This analysis revealed that 57 cases (93%) fit into four major immunophenotypic groups (one histiocytic and three dendritic cell types) utilizing six markers: CD68, LYS, CD1a, S100, CD21, and CD35. The four (7%) unclassified cases were further classifiable into the above four groups using additional morphological and ultrastructural features. The four groups then included: (i) histiocytic sarcoma (n=18) with the following phenotype: CD68 (100%), LYS (94%), CD1a (0%), S100 (33%), CD21/35 (0%). The median age was 46 years. Presentation was predominantly extranodal (72%) with high mortality (58% dead of disease (DOD)). Three had systemic involvement consistent with 'malignant histiocytosis'; (ii) Langerhans cell tumour (LCT) (n=26) which expressed: CD68 (96%), LYS (42%), CD1a (100%), S100 (100%), CD21/35 (0%). There were two morphological variants: cytologically typical (n=17) designated LCT; and cytologically malignant (n=9) designated Langerhans cell sarcoma (LCS). The LCS were often not easily recognized morphologically as LC-derived, but were diagnosed based on CD1a staining. LCT and LCS differed in median age (33 versus 41 years), male:female ratio (3.7:1 versus 1:2), and death rate (31% versus 50% DOD). Four LCT patients had systemic involvement typical of Letterer-Siwe disease; (iii) follicular dendritic cell tumour/sarcoma (FDCT) (n=13) which expressed: CD68 (54%), LYS (8%), CD1a (0%), S100 (16%), FDC markers CD21/35 (100%), EMA (40%). These patients were adults (median age 65 years) with predominantly localized nodal disease (75%) and low mortality (9% DOD); (iv) interdigitating dendritic cell tumour/sarcoma (IDCT) (n=4) which expressed: CD68 (50%), LYS (25%), CD1a (0%), S100 (100%), CD21/35 (0%). The patients were adults (median 71 years) with localized nodal disease (75%) without mortality (0% DOD). In conclusion, definitive immunophenotypic classification of histiocytic and accessory cell neoplasms into four categories was possible in 93% of the cases using six antigens detected in paraffin-embedded sections. Exceptional cases (7%) were resolvable when added morphological and ultrastructural features were considered. We propose a classification combining immunophenotype and morphology with five categories, including Langerhans cell sarcoma. This simplified scheme is practical for everyday diagnostic use and should provide a framework for additional investigation of these unusual neoplasms.

Improvements to B cell clonality analysis using PCR amplification of immunoglobulin light chain genes.

AIMS: Clonality analysis using polymerase chain reaction (PCR) amplification of the immunoglobulin heavy chain (IgH) gene is an important aid to the diagnosis of B cell lymphoproliferative diseases. However, the method has a relatively high false negative rate. In an attempt to improve detection rates simple PCR strategies for clonality analysis of B cell populations using amplification of Ig light chain genes have been developed. METHODS: Novel PCR protocols, designed to amplify Ig kappa and Ig lambda light chain genes, were evaluated using high molecular weight DNA samples from 28 selected cases of B cell lymphoma with known light chain expression and 12 reactive lymphoid specimens. Products were run on 10% polyacrylamide minigels using heteroduplex analysis. Conventional IgH PCR analysis was also performed. Twelve randomly selected formalin fixed, paraffin wax processed samples from cases submitted for molecular genetic analysis were also studied. RESULTS: Polyclonal products were seen in all reactive lymphoid samples. Using Ig kappa PCR, 24 of 28 lymphomas, including four of five IgH negative cases, displayed monoclonal patterns. Using Ig lambda PCR, eight of 12 Ig lambda expressing tumours, including two of five IgH negative cases, showed monoclonal patterns. Standard IgH PCR demonstrated monoclonality in 23 of 28 B cell lymphomas. The detection rate was improved to 27 of 28 lymphomas using heavy and light chain PCR. Efficient amplification was achieved using paraffin wax processed samples, seven of which showed monoclonality compared with eight using IgH PCR. CONCLUSIONS: Ig light chain PCR, used in conjunction with heavy chain analysis, enables improved detection of B cell monoclonality using routine histological specimens and can provide additional clone specific markers for the study of the biology of B cell tumours.

MALT Lymphomas.

This review addresses the biology and the treatment of lymphomas arising from mucosa-associated lymphoid tissue (MALT). This entity, first described in 1983, represents about 8% of all non-Hodgkin's lymphomas and was recently re-classified as "extranodal marginal zone lymphomas of MALT-type." The term marginal zone lymphoma (MZL) encompasses the three closely related lymphoma subtypes of nodal, primary splenic and extranodal lymphomas of MALT type: the latter represent the vast majority of MZL. These lymphomas arise at different anatomic sites, are composed of mature B-cells lacking expression of CD5 and CD10, often present with overlapping morphologic features, but typically quite distinct clinical behaviors. Only very recently cytogenetic/molecular genetic observations have underlined the distinctiveness of these three lymphoid neoplasms, which in both the R.E.A.L. and WHO-classifications are included in the general term of MZL. MALT lymphomas arise in numerous extranodal sites, but gastric MALT lymphoma is the most common and best studied and is, therefore, the paradigm for the group as a whole. Dr. Isaacson describes the principal histological features of these lymphomas, including criteria to distinguish this entity from other small B-cell lymphomas. Several lines of evidence suggest that gastric lymphoma arises from MALT acquired as the result of aH. pyloriinfection. However, at least 1/3 of cases do not respond to eradication ofH. pylori. Very recent data suggest that both t(11;18) (q21;q21) and bcl10 nuclear expression are associated with failure to respond to this treatment. Dr. Gascoyne discusses the biologic function of proteins deregulated through the different translocations, which play a role in pathogenesis of MALT lymphomas, emphasizing particularly their influence in disrupting the apoptotic pathway. Dr. Zucca reviews findings suggesting that MALT lymphoma is an antigen driven neoplasm. He also presents specific guidelines for treatment of gastric lymphomas trying to shed some light on the amazingly inconsistent and confusing data in the literature. Taking advantage on the more than 300 non-gastric MALT lymphomas collected by the International Extranodal Lymphoma Study Group (ILESG), Dr. Cavalli compares gastric lymphomas with those arising in many other sites. Overall, the data presented in this session will underline the fact, that MALT lymphomas are characterized by some unique biological properties.

Myeloperoxidase expression by histiocytes in Kikuchi's and Kikuchi-like lymphadenopathy.

Forty-five examples of Kikuchi's lymphadenitis (KL), 5 Kikuchi-like lupus erythematosus lymphadenopathies, 25 nonnecrotizing lymphadenitidies (5 toxoplasmic, 5 sarcoid-like, 6 dermatopathic, 4 suppurative, 3 tubercular, 2 with sinus histiocytosis), 4 examples of hyaline-vascular Castleman disease (CD), 2 plasmacytoid monocyte tumors (PM-Ts), and 61 accessory cell neoplasms were studied by a panel of antibodies, including the PG-M1 (against a macrophage-restricted CD68 epitope) and a polyclonal anti-myeloperoxidase (MPO). In KL and Kikuchi-like lupus erythematosus lymphadenopathies, 25 to 75% of CD68(+) histiocytes co-expressed MPO. This did not occur in nonnecrotizing lymphadenitidies and accessory cell neoplasms. MPO(+)/CD68(+) elements corresponded to nonphagocytosing mononuclear cells and some crescentic macrophages and phagocytosing histiocytes. Typical PMs were MPO(-)/CD68(+) in all cases, including CD and PM-T. Our observations suggest that in KL and KL-like lymphadenopathies: 1) MPO(+)/CD68(+) blood monocytes might be attracted into tissues because of the lack or paucity of granulocytes and the need of MPO for oxidative processes; 2) PMs are more likely to be involved in the cytotoxic immune reaction than in phagocytic phenomena; 3) the peculiar phenotype of the histiocytic component can be usefully used for the differentiation from malignant lymphoma and PM-T.

T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10.

The development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a multistep process and can be clinico-pathologically divided into Helicobacter pylori-associated gastritis, low-grade tumors, and high-grade tumors. The molecular events underlying this progression are largely unknown. However, identification of the genes involved in MALT lymphoma-specific t(11;18)(q21;q21) and t(1;14)(p22;q32) has provided fresh insights into the pathogenesis of this disease. T(11;18)(q21;q21) results in a chimeric transcript between the API2 and the MALT1 genes, whereas t(1;14) (p22;q32) causes aberrant nuclear BCL10 expression. Significantly, nuclear BCL10 expression also occurs frequently in MALT lymphomas without t(1;14)(p22;q32), suggesting an important role for BCL10 in lymphoma development. Thirty-three cases of H pylori gastritis, 72 MALT lymphomas, and 11 mucosal diffuse large B-cell lymphomas (DLBCL) were screened for t(11;18)(q21;q21) by reverse transcription-polymerase chain reaction followed by sequencing. BCL10 expression in lymphoma cases was examined by immunohistochemistry. The API2--MALT1 fusion transcript was not detected in H pylori gastritis and mucosal DLBCL but was found in 25 of 72 (35%) MALT lymphomas of various sites. Nuclear BCL10 expression was seen in 28 of 53 (53%) of MALT lymphomas. Of the gastric cases, the largest group studied, the frequency of both t(11;18)(q21;q21) and nuclear BCL10 expression was significantly higher in tumors that showed dissemination to local lymph nodes or distal sites (14 of 18 = 78% and 14 of 15 = 93%, respectively) than those confined to the stomach (3 of 29 = 10% and 10 of 26 = 38%). Furthermore, t(11;18)(q21;q21) closely correlated with BCL10 nuclear expression. These results indicate that both t(11;18)(q21;q21) and BCL10 nuclear expression are associated with advanced MALT lymphoma and that their oncogenic activities may be related to each other. (Blood. 2001;98:1182-1187)

Follicular dendritic cells in reactive and neoplastic lymphoid tissues: a reevaluation of staining patterns of CD21, CD23, and CD35 antibodies in paraffin sections after wet heat-induced epitope retrieval.

Structural alterations in the meshwork of follicular dendritic cells (FDCs) are frequently found in malignant lymphomas. Formaldehyde fixation and paraffin embedding, however, have long prevented consistent detection of FDCs. Wet heat-induced epitope retrieval in Dako Target Retrieval Solution (TRS) (pH 6.0) enabled the reliable detection of FDCs through CD21, CD23, and CD35 antigens in routinely processed tissues from 11 reactive and 69 neoplastic lymphoproliferations, thus allowing the distribution of the FDCs to be reevaluated. Germinal center FDCs in lymphoid hyperplasias and expanded FDC meshworks in the 8 mantle cell lymphomas, 7 low-grade MALT lymphomas, and 6 low-grade follicular lymphomas were intensely stained with all these markers. In 6 cases of B cell chronic lymphocytic leukemia, tumor cells were CD23+. In four cases of nodular lymphocyte predominance Hodgkin's disease (HD), expanded FDC meshwork's sharply delineating negative tumor cells and their rosetting T cell, were revealed mainly with the CD21 and CD35 antibodies. Follicular dendritic cells were also demonstrated in 11 cases of grade I nodular sclerosing HD, including follicular HD. Striking dendritic cell clusters were revealed with all 3 antibodies in 9 angioimmunoblastic T cell lymphomas. Sparse or no FDC meshworks were detected in the 4 cases of grade II nodular sclerosing HD, 5 follicular lymphomas with high-grade transformation, and 5 T cell-rich B cell lymphomas. CD35 immunostaining showed the most consistent labeling in the four FDC sarcomas studied in the current article. Reproducible demonstration of FDCs in routinely processed paraffin sections with CD21, CD23, and CD35 antibodies, as presented here, provides invaluable pieces of information in the diagnosis of lymphoproliferative disorders.

Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders.

In a previous study, it was shown that the Kaposi sarcoma-associated herpesvirus (KSHV) was specifically associated with monotypic (IgMlambda) plasmablasts in multicentric Castleman disease (MCD). The plasmablasts occur as isolated cells in the mantle zone of B-cell follicles but may form microlymphoma or frank plasmablastic lymphoma. To determine the clonality and cellular origin of the monotypic plasmablasts, the rearranged Ig genes in 13 patients with KSHV-related MCD, including 8 cases with microlymphomas and 2 with frank lymphomas, were studied. To investigate the role of the interleukin 6 (IL-6) receptor signaling in the pathogenesis of MCD and associated lymphoproliferative disorders, viral IL-6 and human IL-6 receptor expression was examined. KSHV-positive plasmablasts were polyclonal in MCD-involved lymphoid tissues in all cases and microlymphomas in 6 of 8 cases. Monoclonal KSHV-positive plasmablasts were seen in microlymphomas of 2 cases and in both frank lymphomas. Despite their mature phenotype, KSHV-positive plasmablasts did not harbor somatic mutations in the rearranged Ig genes, indicating origination from naive B cells. Viral IL-6 was expressed in 10% to 15% of KSHV-positive plasmablasts, whereas the human IL-6 receptor was expressed in most KSHV-positive cells. Thus, KSHV infects monotypic but polyclonal naive B cells and is associated with a range of lymphoproliferative disorders from polyclonal isolated plasmablasts and microlymphomas to monoclonal microlymphoma and frank plasmablastic lymphomas in MCD patients. Activation of the IL-6 receptor signaling pathway may play a role in differentiation of KSHV-infected naive B cells into plasmablasts and development of lymphoproliferative lesions. (Blood. 2001;97:2130-2136)

Cells of the marginal zone--origins, function and neoplasia.

Splenic marginal zone B cells of humans and mice are anatomically positioned with specialized macrophages, dendritic and endothelial cells. Together, they function as the first line of defense against blood borne pathogens with a low triggering threshold for B cells providing a rapid proliferative and antibody response to infections. In humans, B cells with similar cytology and physical relations to follicles are found in lymph nodes and Peyer's patches. However, they also develop in mucosa-associated lymphoid tissue (MALT) and other sites, such as the thyroid and salivary gland, that normally lack organized lymphoid tissue. Chronic antigenic stimulation at these sites or in response to infection with Hepatitis C provides the milieu for mutations at FAS, API2/ML, TP53 and INK4a/p19ARF and the development of marginal zone lymphomas (MZL) in node, spleen and MALT. Only splenic MZL are seen in mice. A reduced threshold for triggering to proliferation may predispose the marginal zone B cell to neoplasia with mutations in genes regulating apoptosis playing a leading role.

Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy.

20-30% of gastric mucosa-associated lymphoid tissue (MALT) lymphoma associated with Helicobacter pylori do not regress after antibiotic therapy. Regression can be assessed only by extended follow-up. To assess whether t(11;18, q21;q21), which results in a chimeric transcript between the AP12 and MLT genes, predicts lymphoma resistance to antibiotic therapy, we screened for the fusion transcript with RT-PCR in ten responsive and 12 non-responsive gastric MALT lymphomas. The AP12-MLT transcript was detected in nine (75%) of 12 patients non-responsive to antibiotic therapy but not in responsive patients. Most H pylori-associated gastric MALT lymphomas that do not respond to antibiotic therapy are associated with t(11;18, q21;q21).